The development and function of lungresident macrophages and dendritic cells

Size: px
Start display at page:

Download "The development and function of lungresident macrophages and dendritic cells"

Transcription

1 I m m u n o l o g y o f t h e l u n g r e v i e w The development and function of lungresident macrophages and dendritic cells Manfred Kopf 1, Christoph Schneider 1,2 & Samuel P Nobs 1 Gas exchange is the vital function of the lungs. It occurs in the alveoli, where oxygen and carbon dioxide diffuse across the alveolar epithelium and the capillary endothelium surrounding the alveoli, separated only by a fused basement membrane mm in thickness. This tenuous barrier is exposed to dangerous or innocuous particles, toxins, allergens and infectious agents inhaled with the air or carried in the blood. The lung immune system has evolved to ward off pathogens and restrain inflammation-mediated damage to maintain gas exchange. Lung-resident macrophages and dendritic cells are located in close proximity to the epithelial surface of the respiratory system and the capillaries to sample and examine the air-borne and bloodborne material. In communication with alveolar epithelial cells, they set the threshold and the quality of the immune response. The human respiratory tract has a tree-like organization with a trachea connecting to branched airways that terminate in millions of highly vascularized and thin-walled alveoli, the terminal units where the gas exchange of oxygen and carbon dioxide occurs. The surface area of the lungs of a healthy human adult is around 90 m 2, which is relatively large compared with that of the gut (10 m 2 ) and the skin (2 m 2 ) 1. In addition, the surface area of the pulmonary capillaries that encompass the alveoli is about 140 m 2. The distal airways, including bronchioles and alveoli, filter around 8,000-9,000 liters of air every day and are for that reason continuously exposed to a variety of inhaled solid and liquid particles, allergens and airborne microbes, which are taken up and removed mainly by lung-resident macrophages and dendritic cells (DCs). In the absence of an infectious organism, this process usually occurs in a tolerogenic and anti-inflammatory mode and is controlled by resident DC subsets, regulatory T cells and lung epithelial cells 2 6. Inappropriate acute or long-term inflammatory responses are the cause of various diseases such as edema, asthma, fibrosis and emphysema, which damage the thin-walled organ and result in impaired gas exchange and possibly life-threatening lung failure. Even after infection or damage of the epithelial barrier, clearance of the pathogen and repair of the tissue must be well controlled and inflammation must be restrained. It is the crosstalk of antiinflammatory alveolar macrophages (AMs), lung DCs and airway epithelial cells that is responsible for this balancing act. Insights into the development of AMs and lung DCs, as well as the mechanisms that ensure immunity and minimize inflammation, will be the focus of this Review. 1 Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology Zurich, Zurich, Switzerland. 2 Present address: Howard Hughes Medical Institute, University of California San Francisco, San Francisco, California, USA. Correspondence should be addressed to M.K. (manfred.kopf@ethz.ch). Received 18 September; accepted 10 November; published online 18 December 2014; doi: /ni.3052 Lung-resident DCs The DC compartment in the lung is made up of cells of various origins and functions, which form a complex network of sentinel cells. Lung DCs can be categorized as conventional DCs (cdcs), plasmacytoid DCs (pdcs) and monocyte-derived DCs (modcs), which each represent an independent developmental lineage. Functionally, these lung-resident DC subsets have been described as fulfilling distinct and overlapping functions, as discussed in detail below. Generally, lung cdcs and modcs can be identified by high expression of the integrin CD11c and major histocompatibility complex (MHC) class II. For the exclusion of contamination by AMs, due to their high CD11c expression, an AM marker (such as Siglec F) or autofluorescence must be included as well during such identification. cdcs can then be categorized as cells that express the integrin CD103 or the integrin CD11b. Due to the fact that modcs share with CD11b + cdcs various commonly used markers, the Fc receptors CD64 and/or FcεRIα must further be used to distinguish those two subsets. Finally, pdcs can be identified by intermediate expression of CD11c as well as a high expression of the pdc marker PDCA-1 and B cell associated marker B220 (Table 1). The unambiguous characterization of myeloid cell subsets in the lung and other organs will be facilitated in future through the use of high-dimensional analysis by antibody-based single-cell mass spectrometry (CyTOF) 7,8. The development of lung DCs DC development takes place in the bone marrow and is a continuously occurring process due to the requirement for constant replenishment of mature DCs in peripheral tissues. For cdc development, hematopoietic stem cells develop through early progenitors into more lineage-restricted macrophage-dc progenitors 9, which further differentiate into common DC progenitors (CDPs) 10,11. Evidence has questioned this model, however, and has suggested direct development of CDPs from early progenitors without an macrophage-dc progenitor intermediate stage 12. CDPs are the first progenitors restricted to the

2 Table 1 Surface molecule expression on lung DC subsets and macrophages CD103 + cdcs CD11b + cdcs modcs pdcs AMs IMs CD (ref. 19) + (ref. 24) (ref. 24) (ref. 7) + (ref. 7) + (ref. 7) DNGR-1 (CLEC9A) +++ (ref. 20) (refs. 20,55) (refs. 20,55) (ref. 20) (ref. 20) (ref. 20) CD207 + (ref. 19) (ref. 19) (ref. 19) (ref. 154)? SIRPα (ref. 155) + (ref. 155) + (ref. 155) (ref. 7) + (ref. 7) + (ref. 7) CD64 (ref. 24) (ref. 24) + (ref. 24) (ref. 7) + (ref. 7) (ref. 7) MerTK (ref. 7) + (ref. 7) ++ (ref. 7) (ref. 7) ++ (refs. 7,44,143) (ref. 7); + (ref. 44) PDCA-1 (BST2) (ref. 7) (ref. 7) (ref. 7) +++ (ref. 7) + (ref. 7) (ref. 7) Siglec H (ref. 7) (ref. 7) (ref. 7) +++ (ref. 7) (ref. 7) (ref. 7) Siglec F (ref. 24) (ref. 24) (ref. 24) (ref. 24) +++ (refs. 74,75) CD (ref. 33) ++ (ref. 33) + (ref. 33) + (ref. 7) + (ref. 7) + (ref. 7) CD11c +++ (ref. 24) +++ (ref. 24) +++ (ref. 24) + (ref. 7) +++ (refs. 7,73,74,75) + (refs. 7,73) Ly6C (ref. 7) (ref. 7) + (ref. 24) + (ref. 24) + (ref. 7) + (ref. 7) F4/80 + (ref. 19) ++ (ref. 19) +++ (ref. 19) + (ref. 7) +++ (refs. 7,74,75) ++ (ref. 7) MHC class II +++ (ref. 19) +++ (ref. 24) +++ (ref. 24) + (ref. 7) + (refs. 7,73) +++ (refs. 7,73) CD11b + (ref. 19) +++ (ref. 24) +++ (ref. 24) + (ref. 7) + (ref. 7,44,74,75) + (ref. 7) Expression of characteristic surface molecules (far left) on lung DC subsets and macrophages, from high (+++) to low (+) to absent ( ).? indicates still unclear. DC lineage. CDPs further give rise to pre-dcs 13,14, which migrate from the bone marrow to peripheral organs and locally differentiate into mature cdcs (Fig. 1). In general, the process outlined above is controlled by the interplay of global and tissue-specific factors, which leads to the establishment of an organ-specific DC compartment. The cytokine (the ligand for the receptor tyrosine kinase Flt3) has been recognized as a hallmark of various steps of DC development 15, including promoting commitment to the DC lineage at early precursor stages 16,17 and inducing the differentiation and proliferation of CDPs and pre-dcs in the bone marrow as well as of pre-dcs in peripheral organs 18. Development of the pulmonary cdc compartment is thought to occur similarly to such development in other peripheral organs, but some features are different from those of other nonlymphoid organs. Pre- DCs are thought to enter the lung tissue and differentiate locally into mature DC subsets. Cells that phenotypically resemble pre-dcs have indeed been found to be present in the lungs 19, but so far it has not been possible to formally demonstrated that these cells give rise to pulmonary cdcs in situ. Experiments with parabiosis and the thymidine analog BrdU have also demonstrated that the turnover of lung DCs is considerably lower than that of other nonlymphoid tissues DCs, which correlates with a relatively low proliferation of mature cells in the steady state 19. Fate-mapping systems have also shown that while almost all lung CD103 + DCs are CDP derived, this is not the case for CD11b + cdcs, for which only about 50% of cells have been found to be of CDP origin 20. The additional developmental pathway for lung CD11b + DCs in the steady state still remains to be elucidated. Furthermore, despite the strong evidence for the CDP origin of CD103 + DCs in particular, adoptive-transfer studies have shown that monocytes may also give rise to these cells, although there is no strong evidence that this happens during homeostasis 21. The development of mature pulmonary cdcs and pdcs is dependent on. CD11b + cdcs are lower in abundance and CD103 + DCs are almost completely absent in Flt3l / and Flt3 / mice 19,24. This correlates with much higher expression of in the lungs than in other tissues, and this expression is of nonhematopoietic origin, probably derived from epithelial cells 22. Pre-DCs are still present at a lower frequency in the lungs of Flt3l / mice 19, which suggests that acts on the differentiation and also the proliferation of pre-dcs in situ, and possibly also drives the proliferation of mature DCs themselves. To complicate matters, there are also indications that dependence on is restricted to cdcs in the lung parenchyma, while the development of cdcs in the conducting airways is not affected by loss of 23. is also dispensable for development of lung modcs 24. Another tissue-specific factor that controls pulmonary DC development is GM-CSF 25. This growth factor is required for the development of CD103 + DCs in neonatal mice. However, in adult mice, GM-CSF has been found to upregulate CD103 expression on CD103 + CD11b DCs while being largely dispensable for their development unless revealed under competitive conditions in mixed bone marrow chimeras harboring both wild-type DCs and GM-CSF-deficient DCs 26,27. cdc subsets typically express lineage-specific transcription factors (such as Zbtb46) 28,29, which are required for their development and function. Lung CD103 + DCs are dependent on the transcription factor BATF3 for their generation in the steady state, a dependence shared with CD8α + DCs in lymphoid organs 30,31. However, under prolonged inflammatory conditions, such as pulmonary mycobacterial infection, other members of the BATF family may substitute for BATF3, and some CD103 + DCs can still develop through a mechanism based on interleukin 12 (IL-12) and interferon-γ (IFN-γ) 32. CD103 + DCs are also dependent on the transcription factors IRF8 and Id2 for their development 19. Similarly, lung CD11b + DCs are dependent on the transcription factor IRF4 (ref. 33) (Fig. 1). The development of lung-resident pdcs has not been addressed specifically thus far, but some general mechanisms of pdc development have been identified. In contrast to cdcs, pdcs fully develop in the bone marrow and subsequently migrate to the peripheral organs 34. has an essential role in the generation of pdcs in the bone marrow 35, in contrast to its role in the generation of cdcs, for which it acts mainly in the periphery to drive the differentiation and proliferation of pre-dcs and mature cdcs 18. In the bone marrow, pdc development is supported by other pleiotropic cytokines, such as M-CSF 36, IL-7 (ref. 37) and thrombopoietin 38, that act together with. The generation of pdcs is critically dependent on a set of transcription factors, including IRF8 (ref. 39) and STAT3 (ref. 40), downstream of Flt3 and E2-2 (ref. 41). For the proper maturation of pdcs in the periphery, the transcription factor Runx2 is also required 42. GM-CSF and signaling via STAT5 inhibit pdc generation via the suppression of IRF8 (ref. 43). modcs have been only found to be present in the steady state in lungs, as these cells have long been hard to distinguish from CD11b + cdcs due their similar surface markers 24,33. Because of their monocyte origin, modcs are also dependent on the same factors that monocytes depend on for their development. These include the chemokine receptor CCR2 (ref. 24) and the cytokine CSF-1 (ref. 19). Because so VOLUME 16 NUMBER 1 JANUARY 2015 nature immunology

3 far researchers have been unable to separate modcs from CD11b + cdcs, it remains to be determined which other factors are specifically required for the development of lung-resident modcs. A population of Ly6C + blood monocytes has been described as migrating in the steady state from the blood to the lungs (and other tissues) and from there to the lymph nodes without differentiating into DCs or macrophages 44. Further studies addressing the functions of this population, tentatively called tissue monocytes, are warranted. Overall, greater understanding about general aspects of DCs development has been gained in recent years. However, it is not yet well understood how the organ-specific makeup of the DC compartment is achieved and which factors control this process. Further research in this area will be necessary. Lung DC function Foreign materials and pathogens are constantly inhaled into the lungs, and lung-resident DCs are crucial for initiating appropriate immune responses to deal with these challenges. In the lungs, DCs are situated mainly at the basolateral side of the epithelium, and they sample antigens in the lumen of the alveoli and conducting airways 4,45. The sampling activity of DCs depends mainly on their location in the lungs. DCs located in the alveolar septa have many dendritic projections and sample continuously, while DCs in the conducting airways seem to do so rarely 46. Furthermore, a functional division of labor among lung DC subsets is increasingly being elucidated, with each subset exerting both specific functions and overlapping functions under steady-state and inflammatory conditions. A conflicting body of data suggests that lung DC subsets are geared to induce particular helper T cell responses. CD11b + cdcs have been associated with preferential induction of responses of the T H 2 subset 24 and T H 17 subset 33 of helper T cells in a house dust mite model and a fungal model, respectively. Similarly, CD103 + DCs have also been suggested to be biased toward T H 1 responses 47 or T H 2 responses 48. Such findings are probably largely context dependent and emphasize the importance of environmental signals for DC function and plasticity. Generally, respiratory tract infections have been well studied and serve as a good model for elucidating DC subset specific roles in immune responses. In respiratory viral infections, such as infection with influenza virus, the migration of DCs to lung-draining lymph nodes is responsible for the induction of antiviral responses of CD8 + T cells 49 and depends on the chemokine receptor CCR7 (ref. 50) and activation of complement CD103 + DCs have been found to be particularly important for the antiviral responses of CD8 + T cells due to their superior ability to cross-present antigen 53. They have been shown to be nonproductively infected by influenza virus, which allows efficient cross-presentation of viral antigen to naive T cells upon migration to the lung-draining lymph nodes 54. Furthermore, CD103 + DCs have been shown to have the unique ability to take up apoptotic cells and present apoptotic cell derived antigens 55. In addition, it has also demonstrated that CD103 + DCs have antigen MHC class I loading machinery superior to that of CD11b + cdcs 56. By day 5 after infection with influenza virus, CD11b + DCs accumulate to large numbers in draining lymph nodes and become the dominant subset that stimulates CD8 + T cells via costimulation with CD70 (the agonist for the costimulatory receptor CD27) 57. Until recently, CD11b + cdcs could often not be properly separated from modcs, and therefore the precise contributions of these subsets remained to be elucidated. The difference between DC subsets in their CD8 + T cell priming capacity has been further demonstrated by studies showing that CD103 + DCs and CD11b + DCs preferentially induce effector CD8 + T cells and central memory CD8 + T cells, respectively, due to differences in expression of the cell surface marker CD24 on DCs 58. Bone marrow Blood Lung PU.1 HSC CMP STAT3 CDP Pre-DC PU.1 IRF8 PU.1 PU.1 Monocyte CSF1 E2-2 IRF8 CSF1 CSF1 Ikaros cmop MDP pdc Monocyte modc? pdc Runx2 CD103 + DCs CD11b + DCs BATF3 Id2 IRF8 L-Myc CSF2 IRF4 Pre-DC Figure 1 Development of lung DC subsets in the steady state. HSC, hematopoietic stem cell; CMP, common myeloid progenitor; MDP, monocyte-macrophage DC progenitor; cmop, common monocyte progenitor. This suggests a division of labor between CD103 + DCs and CD11b + DCs whereby the former is important for priming of the CD8 + T cell response during an acute infection and the latter is important for the generation of long-term protection. Nevertheless, an absence of CD103 + DCs has not been shown to increase morbidity and mortality during acute infection with influenza virus 27, probably because other mechanisms compensate for the impaired CD8 + T cell responses to limit morbidity 59. Although the functions of modcs present in the lungs at steady state still remain unclear, there is a well-established role for modcs in antiviral responses. During infection with herpes simplex virus, modcs are dispensable for the priming of naive T H 1 cells but are essential for reactivation of these cells in lung tissue 60. Similarly, the lungs of influenza virus infected Ccr2 / mice have fewer CD8 + T cells than do their wild-type counterparts 61. MoDCs have also been found to contribute substantially to pulmonary immunopathology during infection, due to their potent inflammatory function 62. Although pdcs are generally ascribed a potent antiviral role due to their considerable capacity to produce type I interferons, they are surprisingly not critical for effective CD8 + T cell responses or viral clearance following infection with a sublethal dose of influenza virus 49. pdcs even have a detrimental role and enhance mortality during infection with a lethal dose of influenza virus 63. In the latter situation, pdcs preferentially accumulate in the lung-draining lymph nodes and have high expression of the ligand for the cell surface receptor Fas (CD95), which induces apoptosis of antiviral T cells 63. In the steady state, the main role of lung pdcs appears to be maintaining tolerance to inhaled harmless antigens 2,64. It has been shown that the tolerizing capacity of pdcs depends on the subset that expresses the coreceptor CD8α and that lung CD8α pdcs in fact promote airway hyper-responsiveness 65. Nonetheless, cdc subsets have also been associated with the induction of tolerance. Batf3 / mice that lack CD103 + DCs develop enhanced inflammation upon repeated exposure to antigen, which can be explained by their ability to induce de novo differentiation of regulatory T cells (T reg cells) through the Kim Caesar/Nature Publishing Group

4 production of retinoic acid 66. A role for CD11b + cdcs in tolerance remains to be addressed. Maintaining tolerance to innocuous antigens is crucial for the prevention of inflammation in unnecessary circumstances. One situation in which this fails is during allergic asthma. A chronic T H 2 response to environmental allergens such as house dust mites leads to the accumulation of eosinophils, basophils and mast cells in the lungs, as well as goblet cell metaplasia and, eventually, proliferation and hypertrophy of airway smooth muscle cells and thickening of the airways. DCs have been shown to serve an essential role in the initiation and prolongation of this process 4. Depletion of DCs before sensitization abrogates features of asthma 67, and transfer of lung DCs from sensitized mice to naive mice also transfers sensitization 24. Furthermore, DCs are also important during the challenge phase of the response 68. The contributions of the various DC subsets to these processes is also being increasingly elucidated. It has been shown in a house dust mite model that both modcs and CD11b + cdcs are important for sensitization to house dust mites, but CD103 + DCs are dispensable for this 24. Furthermore, modcs do not express CCR7 and thus probably reactivate T H 2 cells in the lungs after antigen challenge 69. AMs under steady-state conditions At least three types of macrophages reside in the lungs: bronchial macrophages, interstitial macrophages (IMs) and AMs. Moreover, intravascular macrophages located on the inner side of capillaries have been described in humans, monkeys, cats and dogs but not in rodents 70. AMs are found in the air space of the alveoli, where they form 90 95% of the cellular content in the steady state. Given that there are several million alveoli and only around one to two million AMs in a mouse lung, not every alveolus contains an AM. Indeed, only a single AM is detected in approximately three alveoli 71, but AMs may travel between alveoli through the connecting pores of Kohn 72. IMs are located in the parenchymal space (interstitium) between adjacent alveoli, where they interact with DCs and interstitial lymphocytes. Through the use of multiparameter flow cytometry or mass cytometry (CyTOF), lung macrophages can be characterized by their expression of the macrophage marker F4/80 and the receptor tyrosine kinase Mertk and can be further separated into CD11c hi Siglec-F hi CD11b lo MHCII lo AMs and CD11c int Siglec- F CD11b hi MHCII hi IMs 7,44,73 75 (Table 1). In contrast to AMs, IMs have been thought to promote immunity by presenting antigen to interstitial T cells. However, in a mouse asthma model, IMs have been shown to promote tolerance and to prevent T H 2-type airway inflammation by IL-10-mediated inhibition of DC activation after exposure to a harmless antigen together with lipopolysaccharide (LPS) 73. In this Review, we will focus mainly on AMs, since knowledge of the ontogeny and function of the other described resident macrophage populations is patchy. We will also avoid discussing inflammatory monocytes that enter the lungs in response to inflammation and infection, since only a few reports have addressed the function of this population specifically. A variety of pathways enable AMs to balance the responses of alveolar epithelial cells (AECs), DCs and lung T cells to environmental cues. Pioneering studies established that AMs suppress immune responses through the inhibition of DC-mediated activation of T cells and production of transforming growth factor-β (TGF-β) Meanwhile, it is well established that TGF-β-induced Foxp3 + T reg cells (it reg cells) inhibit spontaneous and antigen-induced development of T H 2-type airway inflammation 79,80. AMs produce bioactive TGF-β and retinal dehydrogenases 1 and 2, the rate-limiting enzymes for synthesis of the bioactive metabolite retinoic acid from vitamin A (retinol); this results in the generation of Foxp3 + it reg cells from naive CD4 + T cells, which induce tolerance to inhaled innocuous antigens 81. This process occurs in lung tissue and not in the draining lymph nodes and is dependent on presentation of antigen by AMs, not by DCs. AMs lose the ability to induce it reg cells and tolerance when harmless antigens are mixed with allergens known to trigger Toll-like receptor 4 (TLR4) (i.e., extracts from house dust mites and Aspergillus fumigatus). In AMs, the switch from a tolerogenic mode to an inflammatory mode is accompanied by induction of the secretion of IL-1, IL-6, TNF and, surprisingly, TGF-β 81. However, whether the secreted TGF-β is indeed bioactive remains to be investigated. Members of the TGF-β family are secreted in an inactive (latent) form. In the lungs, the integrin α V β 6 expressed on AECs is critical for the activation of latent TGF-β into bioactive TGF-β 82. Integrin β 6 deficient (Itgb6 / ) mice that lack expression of α V β 6 on epithelial cells develop spontaneous inflammation in the lungs (and skin) and age-dependent emphysema 83,84 but are protected from the development of pulmonary edema and fibrosis despite their exaggerated inflammation following acute lung injury induced by bleomycin 82. AMs in Itgb6 / mice promote emphysema due to unrestrained production of the matrix metalloproteinase MMP12 (ref. 85) and show a defect in surfactant lipid catabolism reminiscent of that of GM- CSF-deficient mice or patients with pulmonary alveolar proteinosis (PAP) 86. Several lines of evidence have convincingly demonstrated that the phenotype of Itgb6 / mice results from a defect in the activation of TGF-β and that α V β 6 mediates such activation in a manner dependent on cell-cell contact and the cytoskeleton 82,87. Such data indicate that detachment of AMs from epithelia upon infection may unleash AM inflammation by withdrawal of active TGF-β. Inhibition of pathological airway inflammation occurs via the intercommunication of sessile AMs located in different alveoli through the alveolar epithelium, as suggested by an elegant published study 71. A subset of AMs form gap junctions with AECs through the use of connexin Cx43 hemichannels for docking to each other. Exposure of lung alveoli to LPS induces cyclic and synchronized waves of calcium release from intracellular stores in both AMs and AECs that is dependent on signaling via the receptor for inositol-(1,4,5)- trisphosphate and the kinase Akt. Waves are initiated in AMs and occur periodically (about every 15 minutes) with a progressive increase in size until 24 hours after LPS treatment. Mice with Cx43 deficiency in either AMs or AECs lack such synchronized calcium waves and show increased recruitment of neutrophils to alveoli, production of proinflammatory cytokines and chemokines and mortality following LPS treatment. This indicates that communication between AMs over distance via the epithelium results in synchronized calcium release and protects the host from inflammatory acute lung injury following TLR ligation. The prevention of inflammatory responses is mediated by various inhibitory receptors on AMs, with the ligands expressed on AECs or present in the alveolar fluid; this has also been covered in a published review 88. The interaction of the ligand CD200L on AECs with its receptor CD200R on AMs negatively regulates inflammatory responses induced by TLR triggering. CD200R has more abundant expression on AMs than on splenic or peritoneal macrophages and can be induced in splenic or peritoneal macrophages by ex vivo stimulation with TGF-β, which emphasizes the pivotal regulatory role of TGF-β in the lung 89. Furthermore, interaction of the signal-regulatory protein SIRPα (which mediates a so-called do not eat me signal) on AMs with the globular heads of the surfactant proteins SP-A and SP-D suppresses AM inflammatory responses and phagocytosis 90, which can be overcome by TLR4 triggering that downregulates SIRPα 91,92. VOLUME 16 NUMBER 1 JANUARY 2015 nature immunology

5 AMs in defense The negative signals of the inhibitory receptors are overridden by infection with a pathogen that unleashes the AMs by combined ligation of several pathogen-recognition receptors of the TLR family, C-type lectin family, NLRP family and/or scavenger receptor family 93. AMs are ideally suited to act as first line of innate cellular defense in the lower airways due to their localization in the alveolar lumen, where they are attached to AECs and sample the microbes that are transported toward them by alveolar liquid flow 71. A host of reports have demonstrated a key role for AMs in the defense against bacterial, fungal and viral infections and in the prevention of acute lung injury through the limitation of and restoration of normalcy after infection-mediated damage. By virtue of their potent phagocytic ability 94,95, AMs are essential for the clearance of pulmonary infection with bacteria and fungi, including Streptococcus pneumonia, Mycobacteria tuberculosis, Pseudomonas aeroginosa and Pneumocystis carinii The phagocytic ability of AMs, including the removal of dead cells (efferocytosis), is increased substantially in inflammatory conditions or infections, during which the collectin family molecules SP-A, SP-D and C1q promote phagocytosis as well as inflammation by binding to pathogen-associated molecular patterns or apoptotic cells through their globular heads and to calreticulin-cd91 on AMs with their collagenous tails 90,100. Thus, dependent on the environmental cues, SP-A and SP-D can have pro- or anti-inflammatory effect on AMs, which is mediated by interaction of the tail or the head of the surfactant proteins with different receptors on the AMs (i.e., calreticulin-cd91 or SIRPα). Unlike the Janus-faced activity of SP-A and SP-D, C1q promotes phagocytosis and inflammation but lacks the anti-inflammatory activity. Consistent with that, activation of complement promotes AM-mediated control of pneumococcal infection in models of fulminant infection 101,102. The class A scavenger receptor MARCO prevents fatal pneumonia via the binding, phagocytosis and clearance of S. pneumonia 103. While AMs are ineffective in presenting antigen to T cells due to their low expression of costimulatory molecules 104, they can rapidly transport bacteria from the lungs to lung-draining lymph nodes 105,106. However, the consequences of this transport remain still unclear. Among respiratory viral infections, the best-studied example is infection with influenza virus. The lack of AMs in mice deficient in GM-CSF (Csf2 / mice) or its receptor GM-CSFR (Csf2rb / mice) or depletion of AMs results in impaired clearance of virus and mortality in response to infection with a low dose of influenza virus 27, , while pulmonary overexpression of GM-CSF prevents AM apoptosis and provides resistance to a lethal dose of influenza virus 110,111. AMs protect the host from influenza virus induced morbidity mainly through their ability to phagocytose apoptotic epithelial cells and surfactant phospholipids 112,113, which accumulate in the alveoli during infection with influenza virus and curtail gas exchange. Mice that lack AMs die due to lung failure and hypoxia 27. In addition, AMs limit acute lung injury induced by the proinflammatory response to influenza virus without affecting efficient T cell and B cell responses 27. On the basis of all these data, we hypothesize that virulent strains of influenza virus may induce fatal responses in human patients by interfering with AM function. The interaction of CD200R on AMs with its ligand CD200 on AECs appears to be a major pathway of protection from inflammatory lung injury and morbidity following infection with influenza virus. The expression of both CD200 and CD200R is progressively upregulated during infection with influenza A virus, and their engagement inhibits the production of proinflammatory cytokines and recruitment of leukocytes at the expense of increased viral replication 89. The scavenger receptor MARCO, which is critical for the clearance of pneumococcal infection, transiently inhibits the recruitment of neutrophils and inflammatory responses in the early phase of infection with influenza A virus, which affects viral clearance and increases morbidity by asyet-unknown mechanisms 114. The receptor Trem-1 has high expression on AMs during homeostasis 115. Activation by an as-yet-unknown ligand has been thought to boost TLR-induced inflammatory responses and control of bacterial infection 115. Surprisingly, Trem- 1-deficient mice efficiently control acute pulmonary bacterial and viral infection and undergo less morbidity than wild-type mice after infection with influenza virus, which indicates an anti-inflammatory role rather than a proinflammatory role for Trem-1 (ref. 116). AMs can become infected by influenza virus depending on the pathogenicity of the viral strain 27,54,117. AMs are less able producers of infectious virus than are AECs 117, but they potently upregulate the production of type I interferons 27,118,119 and thereby interfere with viral spread 120, ameliorate morbidity through induction of the interferon-inducible antiviral protein IFITM3 (refs. 121,122), suppress cytokine signaling by upregulation of the inhibitory proteins SOCS1 and SOCS3 on AECs 123, and inhibit the recruitment of neutrophils as well as the production of proinflammatory cytokines 120. Restrained extravasation of lung neutrophils by type I interferons during acute infection with influenza A virus renders mice highly susceptible to post-influenza superinfection with S. pneumoniae 124. Notably, IFN-γ produced by antiviral T cells following infection with influenza virus can inhibit AM-mediated phagocytosis and clearance of a secondary bacterial infection at least partially through downregulation of MARCO 125. The development of AMs Over the past 5 years, various studies addressing the ontogeny of tissue macrophages have laid the foundation for a change in the longheld dogma of mononuclear phagocyte development, which taught that bone marrow derived circulating blood monocytes constantly enter tissues to replenish resident macrophages. Meanwhile, it is well accepted that many tissue macrophage subsets, including lung AMs, arise from embryonic progenitors that seed the organs and mature locally before and shortly after birth. They are maintained by proliferative self-renewal throughout life autonomously from bone marrow derived monocytes in the steady state 126,127. Like many other organs, fetal lungs contain two distinct myeloid populations, F4/80 hi CD11b int fetal macrophages and F4/ 80 int CD11b hi Ly6C + fetal monocytes, which are considered to derive from embryonic hematopoiesis in the yolk sac and fetal liver, respectively Fetal macrophages that are generated during primitive hematopoiesis in the yolk sac appear around embryonic day 8.5 (E8.5) and subsequently colonize tissues via the blood circulation 132. Fetal monocytes are generated in the fetal liver around E12 and subsequently migrate to embryonic tissues, where they appear around E14 (ref. 128). Both of those populations can be clearly identified in fetal lungs at E14.5 E18.5 (refs. 74,75). While the number of fetal macrophages remains relatively constant between E17 until around 1 week after birth, fetal lung monocyte populations expand dramatically, accompanied by a profound change in expression of characteristic surface markers during this period. They successively increase their expression of CD11c, Siglec-F, F4/80 and CD64 and concomitantly downregulate their expression of Ly6C and CD11b until they reach the mature stage defined as F4/80 hi CD11c hi SiglecF hi CD64 hi CD11b lo Ly6C lo AMs with bright autofluorescence (Fig. 2). Fetal monocytes (F4/80 lo ) are able to develop to mature AMs upon adoptive transfer into the lungs of

6 newborn mice, but fetal macrophages (F4/80 hi ) are not 74,75,133. After perinatal development, mature AMs are maintained by homeostatic proliferation 74,134 and self-renew without substantial contribution by immigrating monocyte precursor cells, as suggested by the intact AM compartment in leukemic patients with decreased or absent blood monocytes 135. The proliferative capacity of mature AMs was already reported 40 years ago 136,137. Today, compelling evidence from several studies using genetic fate-mapping approaches, parabiosis and partial-body irradiation has demonstrated that progenitor cells derived from hematopoietic stem cells in adults do not contribute much to AMs under steady-state conditions 74,134,138,139. However, they have the ability to differentiate into functional AMs under certain conditions, as shown by transfer of bone marrow hematopoietic stem cells into lethally irradiated recipients with ablated tissue macrophages 27,74,134. Impaired self-renewal ability of AMs due to aging or certain environmental cues might also result in the replenishment of AMs by circulating blood monocytes, as has been suggested for cardiac macrophages 140. The molecular mechanisms that underlie the self-renewal of terminally differentiated tissue macrophages have not yet been well characterized. Downregulation of the transcription factors MafB and c-maf and fine-tuned joint upregulation of c-myc and KLF4 might be involved in this process. Mature macrophages deficient in both MafB and c-maf display unlimited non-tumorigenic self-renewal due to elevated expression of c-myc and KLF4 (ref. 141), two factors critically involved in stem-cell renewal 142. Factors that regulate AM development A hallmark of tissue-resident macrophage subsets is their diversity in function that is associated with distinct gene-expression signatures 126,127,143. The degree of transcriptional diversity between different tissue macrophages is greater than that between DCs of different subsets and organs 143. The development of distinct tissue macrophage subsets from a common yolk sac or fetal liver derived progenitor indicates that the tissue niche may direct the development of the progenitors locally by induction of a distinct transcriptional program required to serve organ physiology. The development of PAP in Csf2 / mice and Csf2rb / mice provided first evidence of a critical role for this cytokine in lung homeostasis 144, a result later confirmed by the finding of mutations in the genes encoding the α-chain of GM-CSFR and the common β-chain or autoantibodies to GM-CSF in human patients with acquired or congenital PAP 145. The observation of macrophages engorged with lipids in lungs of Csf2 / mice suggests that AMs are immature and defective in surfactant catabolism 146. However, several reports have demonstrated, through the use of multicolor flow cytometry, that Csf2 / and Csf2rb / mice are completely devoid of AMs 27,74,134, which indicates that lipid-loaded cells found in the lungs of these mutant mice are a different type of myeloid cell. In the absence of GM-CSF, differentiation of the AM progenitor is already abrogated in the fetal lungs at around E17, which indicates that GM-CSF is instrumental for licensing AM development. In the mouse fetus, the highest GM-CSF expression is found in the lungs, where stromal cells are the main source that provide it in a paracrine manner to fetal monocytes 74,75. GM-CSF instructs lung fetal monocyte differentiation shortly before and after birth through activation of the nuclear receptor PPAR-γ, which controls the transcriptional program intrinsically required for the differentiation and function of AMs, including cholesterol metabolism, β-oxidation of fatty acids, lipid transport, storage and degradation 75. Accordingly, mice with prenatal deletion of Pparg lack AMs and develop severe PAP similar to that of Csf2 / mice 75. In addition, patients with PAP have also been found to have Stages during ontogeny F4/80 CD11c Siglec F Phenotype CD64 CD11b Ly6C Fetal monocyte Alveolar epithelium Pre-AM Mature AM PPAR-γ PPAR-γ PPAR-γ Bach2 E15 E18 GM-CSF E19 D3 >D4 Figure 2 Development of AMs. Fetal monocytes seed the lungs at around E15. The production of GM-CSF (CSF2) by AECs induces expression of PPAR-γ in fetal monocytes, which instructs the development and function of AMs. There is gradual up- and downregulation of cell surface markers during AM ontogeny. D3 and D4, day 3 and day 4 after birth. low expression of PPAR-γ in AMs 147. The metabolism of lipid and cholesterol in mature AMs is also controlled by the B lymphoid transcriptional repressor Bach2; this involves at least in part upregulation of the ATP-binding cassette transporters ABCA1 and ABCG1, which are responsible for excess efflux of cholesterol from macrophages. Bach2-deficient mice show accumulation of lipids in AMs and development of PAP 148 similar to that of mice that lack ABCA1 or ABCG1 (refs ) (Fig. 2). Studies of mice with transgenic expression of Cre recombinase from the gene encoding LysM (LysM-Cre) for myeoid cell specific deletion of loxp-flanked Pparg alleles have found only relatively mild and age-dependent PAP in the mice 152, explained by inefficient gene deletion in fetal myeloid progenitor cells together with a competitive disadvantage in the population expansion of myeloid progenitors in which Pparg was deleted compared with that of wild-type myeloid progenitors 75. That study warrants caution for the use of LysM-Cre for conditional deletion of genes involved in the development of embryoderived tissue macrophages and the interpretation of results obtained with such mice. The role and fate of fetal macrophages in the lungs is currently not understood. A published report suggests that they may be involved in lung morphogenesis and airway branching between E10 and E18, which is disturbed when fetal macrophages are exposed to LPS 153. However, fetal monocytes and macrophages were not distinguished in that study. Regardless of what proves true, the results indicate that an infection in late pregnancy may be detrimental for lung development. Perspective Overall, published work has shed light on the complex interactions of lung AMs and DCs in both health and disease, but many questions about their biology remain to be addressed. Future directions of research should focus on elucidating the environmental and tissue-specific signals that regulate the occupation of lung niches by cells of the mononuclear phagocyte network. Specifically, the signals that control the homeostatic renewal of AMs as well as their intricate relationship with alveolar epithelium need to be addressed in more detail. The adoptive transfer of fetal monocytes into AM-deficient Kim Caesar/Nature Publishing Group VOLUME 16 NUMBER 1 JANUARY 2015 nature immunology

7 mice will be an excellent tool with which to address AM-intrinsic factors that control development and function in homeostasis and inflammation. Similarly, further studies are needed to elucidate the mechanisms that control the development of lung-specific DC subsets and how tissue-specific identity and function is conferred on these cells. Naturally, this will raise a more general question about the plasticity and adaptability of DC subpopulations that reside in various organs. Environmental factors such as the microbiota are known to serve key roles at mucosal surfaces in regulating the function of cells of the immune system, and for the lungs, this component s contribution to immune responses has largely not been addressed so far. The interactions of commensal microbes with AMs and DCs as well as with epithelial cells, not only in the steady state but also under inflammatory conditions, will be of key importance for understanding the pathogenesis of many pulmonary diseases. New advances in imaging technology will pave the way for better understanding of temporal and local AM and DC function and will allow real-time monitoring of key biological processes, such as antigen uptake and migration by DCs, as well as surfactant catabolism and processing by AMs. Acknowledgments Supported by the Swiss National Science Foundation ( /1) and Swiss Federal Institute of Technology Zürich (ETH ). COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests. Reprints and permissions information is available online at reprints/index.html. 1. Revoir, W.H. & Bien, C.-T. Respiratory Protection Handbook (CRC Press, 1997). 2. de Heer, H.J. et al. Essential role of lung plasmacytoid dendritic cells in preventing asthmatic reactions to harmless inhaled antigen. J. Exp. Med. 200, (2004). 3. Hintzen, G. et al. Induction of tolerance to innocuous inhaled antigen relies on a CCR7-dependent dendritic cell-mediated antigen transport to the bronchial lymph node. J. Immunol. 177, (2006). 4. Lambrecht, B.N. & Hammad, H. Lung dendritic cells in respiratory viral infection and asthma: from protection to immunopathology. Annu. Rev. Immunol. 30, (2012). 5. Lo, B., Hansen, S., Evans, K., Heath, J.K. & Wright, J.R. Alveolar epithelial type II cells induce T cell tolerance to specific antigen. J. Immunol. 180, Strickland, D.H. et al. Reversal of airway hyperresponsiveness by induction of airway mucosal CD4 + CD25 + regulatory T cells. J. Exp. Med. 203, (2006). 7. Becher, B. et al. High-dimensional analysis of the murine myeloid cell system. Nat. Immunol. 15, (2014). 8. Ornatsky, O., Baranov, V.I., Bandura, D.R., Tanner, S.D. & Dick, J. Multiple cellular antigen detection by ICP-MS. J. Immunol. Methods 308, (2006). 9. Fogg, D.K. et al. A clonogenic bone marrow progenitor specific for macrophages and dendritic cells. Science 311, (2006). 10. Onai, N. et al. Identification of clonogenic common Flt3 + M-CSFR + plasmacytoid and conventional dendritic cell progenitors in mouse bone marrow. Nat. Immunol. 8, (2007). 11. Naik, S.H. et al. Development of plasmacytoid and conventional dendritic cell subtypes from single precursor cells derived in vitro and in vivo. Nat. Immunol. 8, (2007). 12. Sathe, P. et al. Lymphoid tissue and plasmacytoid dendritic cells and macrophages do not share a common macrophage-dendritic cell-restricted progenitor. Immunity 41, (2014). 13. Naik, S.H. et al. Intrasplenic steady-state dendritic cell precursors that are distinct from monocytes. Nat. Immunol. 7, (2006). 14. Diao, J. et al. In situ replication of immediate dendritic cell (DC) precursors contributes to conventional DC homeostasis in lymphoid tissue. J. Immunol. 176, (2006). 15. Liu, K. et al. In vivo analysis of dendritic cell development and homeostasis. Science 324, (2009). 16. Daro, E. et al. Polyethylene glycol-modified GM-CSF expands CD11b high CD11c high but notcd11b low CD11c high murine dendritic cells in vivo: a comparative analysis with Flt3 ligand. J. Immunol. 165, (2000). 17. Kingston, D. et al. The concerted action of GM-CSF and Flt3-ligand on in vivo dendritic cell homeostasis. Blood 114, (2009). 18. Waskow, C. et al. The receptor tyrosine kinase Flt3 is required for dendritic cell development in peripheral lymphoid tissues. Nat. Immunol. 9, Ginhoux, F. et al. The origin and development of nonlymphoid tissue CD103 + DCs. J. Exp. Med. 206, (2009). 20. Schraml, B.U. et al. Genetic tracing via DNGR-1 expression history defines dendritic cells as a hematopoietic lineage. Cell 154, (2013). 21. Jakubzick, C. et al. Blood monocyte subsets differentially give rise to CD103 + and CD103 pulmonary dendritic cell populations. J. Immunol. 180, Miloud, T., Fiegler, N., Suffner, J., Hammerling, G.J. & Garbi, N. Organ-specific cellular requirements for in vivo dendritic cell generation. J. Immunol. 188, (2012). 23. Walzer, T., Brawand, P., Swart, D., Tocker, J. & De Smedt, T. No defect in T-cell priming, secondary response, or tolerance induction in response to inhaled antigens in Fms-like tyrosine kinase 3 ligand-deficient mice. J. Allergy Clin. Immunol. 115, (2005). 24. Plantinga, M. et al. Conventional and monocyte-derived CD11b + dendritic cells initiate and maintain T helper 2 cell-mediated immunity to house dust mite allergen. Immunity 38, (2013). 25. Greter, M. et al. GM-CSF controls nonlymphoid tissue dendritic cell homeostasis but is dispensable for the differentiation of inflammatory dendritic cells. Immunity 36, (2012). 26. Edelson, B.T. et al. Batf3-dependent CD11b low/ peripheral dendritic cells are GM-CSF-independent and are not required for Th cell priming after subcutaneous immunization. PLoS ONE 6, e25660 (2011). 27. Schneider, C. et al. Alveolar macrophages are essential for protection from respiratory failure and associated morbidity following influenza virus infection. PLoS Pathog. 10, e (2014). 28. Meredith, M.M. et al. Expression of the zinc finger transcription factor zdc (Zbtb46, Btbd4) defines the classical dendritic cell lineage. J. Exp. Med. 209, (2012). 29. Satpathy, A.T. et al. Zbtb46 expression distinguishes classical dendritic cells and their committed progenitors from other immune lineages. J. Exp. Med. 209, (2012). 30. Hildner, K. et al. Batf3 deficiency reveals a critical role for CD8α + dendritic cells in cytotoxic T cell immunity. Science 322, Edelson, B.T. et al. Peripheral CD103 + dendritic cells form a unified subset developmentally related to CD8α + conventional dendritic cells. J. Exp. Med. 207, (2010). 32. Tussiwand, R. et al. Compensatory dendritic cell development mediated by BATF- IRF interactions. Nature 490, (2012). 33. Schlitzer, A. et al. IRF4 transcription factor-dependent CD11b + dendritic cells in human and mouse control mucosal IL-17 cytokine responses. Immunity 38, (2013). 34. Gilliet, M. et al. The development of murine plasmacytoid dendritic cell precursors is differentially regulated by FLT3-ligand and granulocyte/macrophage colonystimulating factor. J. Exp. Med. 195, (2002). 35. McKenna, H.J. et al. Mice lacking flt3 ligand have deficient hematopoiesis affecting hematopoietic progenitor cells, dendritic cells, and natural killer cells. Blood 95, (2000). 36. Fancke, B., Suter, M., Hochrein, H. & O Keeffe, M. M-CSF: a novel plasmacytoid and conventional dendritic cell poietin. Blood 111, Vogt, T.K., Link, A., Perrin, J., Finke, D. & Luther, S.A. Novel function for interleukin-7 in dendritic cell development. Blood 113, (2009). 38. Onai, N. et al. A clonogenic progenitor with prominent plasmacytoid dendritic cell developmental potential. Immunity 38, (2013). 39. Tsujimura, H., Tamura, T. & Ozato, K. Cutting edge: IFN consensus sequence binding protein/ifn regulatory factor 8 drives the development of type I IFNproducing plasmacytoid dendritic cells. J. Immunol. 170, (2003). 40. Laouar, Y., Welte, T., Fu, X.Y. & Flavell, R.A. STAT3 is required for -dependent dendritic cell differentiation. Immunity 19, (2003). 41. Cisse, B. et al. Transcription factor E2 2 is an essential and specific regulator of plasmacytoid dendritic cell development. Cell 135, Sawai, C.M. et al. Transcription factor Runx2 controls the development and migration of plasmacytoid dendritic cells. J. Exp. Med. 210, (2013). 43. Esashi, E. et al. The signal transducer STAT5 inhibits plasmacytoid dendritic cell development by suppressing transcription factor IRF8. Immunity 28, Jakubzick, C. et al. Minimal differentiation of classical monocytes as they survey steady-state tissues and transport antigen to lymph nodes. Immunity 39, (2013). 45. Jahnsen, F.L. et al. Accelerated antigen sampling and transport by airway mucosal dendritic cells following inhalation of a bacterial stimulus. J. Immunol. 177, (2006). 46. Thornton, E.E. et al. Spatiotemporally separated antigen uptake by alveolar dendritic cells and airway presentation to T cells in the lung. J. Exp. Med. 209, (2012). 47. Furuhashi, K. et al. Mouse lung CD103 + and CD11b high dendritic cells preferentially induce distinct CD4 + T-cell responses. Am. J. Respir. Cell Mol. Biol. 46, (2012). 48. Nakano, H. et al. Pulmonary CD103 + dendritic cells prime Th2 responses to inhaled allergens. Mucosal Immunol. 5, (2012).

Question 1. Kupffer cells, microglial cells and osteoclasts are all examples of what type of immune system cell?

Question 1. Kupffer cells, microglial cells and osteoclasts are all examples of what type of immune system cell? Abbas Chapter 2: Sarah Spriet February 8, 2015 Question 1. Kupffer cells, microglial cells and osteoclasts are all examples of what type of immune system cell? a. Dendritic cells b. Macrophages c. Monocytes

More information

ACTIVATION AND EFFECTOR FUNCTIONS OF CELL-MEDIATED IMMUNITY AND NK CELLS. Choompone Sakonwasun, MD (Hons), FRCPT

ACTIVATION AND EFFECTOR FUNCTIONS OF CELL-MEDIATED IMMUNITY AND NK CELLS. Choompone Sakonwasun, MD (Hons), FRCPT ACTIVATION AND EFFECTOR FUNCTIONS OF CELL-MEDIATED IMMUNITY AND NK CELLS Choompone Sakonwasun, MD (Hons), FRCPT Types of Adaptive Immunity Types of T Cell-mediated Immune Reactions CTLs = cytotoxic T lymphocytes

More information

Tolerance, autoimmunity and the pathogenesis of immunemediated inflammatory diseases. Abul K. Abbas UCSF

Tolerance, autoimmunity and the pathogenesis of immunemediated inflammatory diseases. Abul K. Abbas UCSF Tolerance, autoimmunity and the pathogenesis of immunemediated inflammatory diseases Abul K. Abbas UCSF Balancing lymphocyte activation and control Activation Effector T cells Tolerance Regulatory T cells

More information

Effector mechanisms of cell-mediated immunity: Properties of effector, memory and regulatory T cells

Effector mechanisms of cell-mediated immunity: Properties of effector, memory and regulatory T cells ICI Basic Immunology course Effector mechanisms of cell-mediated immunity: Properties of effector, memory and regulatory T cells Abul K. Abbas, MD UCSF Stages in the development of T cell responses: induction

More information

Antigen Presentation and T Lymphocyte Activation. Abul K. Abbas UCSF. FOCiS

Antigen Presentation and T Lymphocyte Activation. Abul K. Abbas UCSF. FOCiS 1 Antigen Presentation and T Lymphocyte Activation Abul K. Abbas UCSF FOCiS 2 Lecture outline Dendritic cells and antigen presentation The role of the MHC T cell activation Costimulation, the B7:CD28 family

More information

T-cell activation T cells migrate to secondary lymphoid tissues where they interact with antigen, antigen-presenting cells, and other lymphocytes:

T-cell activation T cells migrate to secondary lymphoid tissues where they interact with antigen, antigen-presenting cells, and other lymphocytes: Interactions between innate immunity & adaptive immunity What happens to T cells after they leave the thymus? Naïve T cells exit the thymus and enter the bloodstream. If they remain in the bloodstream,

More information

T-cell activation T cells migrate to secondary lymphoid tissues where they interact with antigen, antigen-presenting cells, and other lymphocytes:

T-cell activation T cells migrate to secondary lymphoid tissues where they interact with antigen, antigen-presenting cells, and other lymphocytes: Interactions between innate immunity & adaptive immunity What happens to T cells after they leave the thymus? Naïve T cells exit the thymus and enter the bloodstream. If they remain in the bloodstream,

More information

Medical Virology Immunology. Dr. Sameer Naji, MB, BCh, PhD (UK) Head of Basic Medical Sciences Dept. Faculty of Medicine The Hashemite University

Medical Virology Immunology. Dr. Sameer Naji, MB, BCh, PhD (UK) Head of Basic Medical Sciences Dept. Faculty of Medicine The Hashemite University Medical Virology Immunology Dr. Sameer Naji, MB, BCh, PhD (UK) Head of Basic Medical Sciences Dept. Faculty of Medicine The Hashemite University Human blood cells Phases of immune responses Microbe Naïve

More information

Effector T Cells and

Effector T Cells and 1 Effector T Cells and Cytokines Andrew Lichtman, MD PhD Brigham and Women's Hospital Harvard Medical School 2 Lecture outline Cytokines Subsets of CD4+ T cells: definitions, functions, development New

More information

Lymphoid System: cells of the immune system. Answer Sheet

Lymphoid System: cells of the immune system. Answer Sheet Lymphoid System: cells of the immune system Answer Sheet Q1 Which areas of the lymph node have most CD3 staining? A1 Most CD3 staining is present in the paracortex (T cell areas). This is towards the outside

More information

Cytokines modulate the functional activities of individual cells and tissues both under normal and pathologic conditions Interleukins,

Cytokines modulate the functional activities of individual cells and tissues both under normal and pathologic conditions Interleukins, Cytokines http://highered.mcgraw-hill.com/sites/0072507470/student_view0/chapter22/animation the_immune_response.html Cytokines modulate the functional activities of individual cells and tissues both under

More information

General Overview of Immunology. Kimberly S. Schluns, Ph.D. Associate Professor Department of Immunology UT MD Anderson Cancer Center

General Overview of Immunology. Kimberly S. Schluns, Ph.D. Associate Professor Department of Immunology UT MD Anderson Cancer Center General Overview of Immunology Kimberly S. Schluns, Ph.D. Associate Professor Department of Immunology UT MD Anderson Cancer Center Objectives Describe differences between innate and adaptive immune responses

More information

Innate immunity. Abul K. Abbas University of California San Francisco. FOCiS

Innate immunity. Abul K. Abbas University of California San Francisco. FOCiS 1 Innate immunity Abul K. Abbas University of California San Francisco FOCiS 2 Lecture outline Components of innate immunity Recognition of microbes and dead cells Toll Like Receptors NOD Like Receptors/Inflammasome

More information

ACTIVATION OF T LYMPHOCYTES AND CELL MEDIATED IMMUNITY

ACTIVATION OF T LYMPHOCYTES AND CELL MEDIATED IMMUNITY ACTIVATION OF T LYMPHOCYTES AND CELL MEDIATED IMMUNITY The recognition of specific antigen by naïve T cell induces its own activation and effector phases. T helper cells recognize peptide antigens through

More information

1. The scavenger receptor, CD36, functions as a coreceptor for which TLR? a. TLR ½ b. TLR 3 c. TLR 4 d. TLR 2/6

1. The scavenger receptor, CD36, functions as a coreceptor for which TLR? a. TLR ½ b. TLR 3 c. TLR 4 d. TLR 2/6 Allergy and Immunology Review Corner: Cellular and Molecular Immunology, 8th Edition By Abul K. Abbas, MBBS, Andrew H. H. Lichtman, MD, PhD and Shiv Pillai, MBBS, PhD. Chapter 4 (pages 62-74): Innate Immunity

More information

Adaptive immune responses: T cell-mediated immunity

Adaptive immune responses: T cell-mediated immunity MICR2209 Adaptive immune responses: T cell-mediated immunity Dr Allison Imrie allison.imrie@uwa.edu.au 1 Synopsis: In this lecture we will discuss the T-cell mediated immune response, how it is activated,

More information

The Adaptive Immune Responses

The Adaptive Immune Responses The Adaptive Immune Responses The two arms of the immune responses are; 1) the cell mediated, and 2) the humoral responses. In this chapter we will discuss the two responses in detail and we will start

More information

All animals have innate immunity, a defense active immediately upon infection Vertebrates also have adaptive immunity

All animals have innate immunity, a defense active immediately upon infection Vertebrates also have adaptive immunity 1 2 3 4 5 6 7 8 9 The Immune System All animals have innate immunity, a defense active immediately upon infection Vertebrates also have adaptive immunity Figure 43.2 In innate immunity, recognition and

More information

Tolerance 2. Regulatory T cells; why tolerance fails. Abul K. Abbas UCSF. FOCiS

Tolerance 2. Regulatory T cells; why tolerance fails. Abul K. Abbas UCSF. FOCiS 1 Tolerance 2. Regulatory T cells; why tolerance fails Abul K. Abbas UCSF FOCiS 2 Lecture outline Regulatory T cells: functions and clinical relevance Pathogenesis of autoimmunity: why selftolerance fails

More information

Innate immune regulation of T-helper (Th) cell homeostasis in the intestine

Innate immune regulation of T-helper (Th) cell homeostasis in the intestine Innate immune regulation of T-helper (Th) cell homeostasis in the intestine Masayuki Fukata, MD, Ph.D. Research Scientist II Division of Gastroenterology, Department of Medicine, F. Widjaja Foundation,

More information

2. Innate immunity 2013

2. Innate immunity 2013 1 Innate Immune Responses 3 Innate immunity Abul K. Abbas University of California San Francisco The initial responses to: 1. Microbes: essential early mechanisms to prevent, control, or eliminate infection;

More information

M.Sc. III Semester Biotechnology End Semester Examination, 2013 Model Answer LBTM: 302 Advanced Immunology

M.Sc. III Semester Biotechnology End Semester Examination, 2013 Model Answer LBTM: 302 Advanced Immunology Code : AS-2246 M.Sc. III Semester Biotechnology End Semester Examination, 2013 Model Answer LBTM: 302 Advanced Immunology A. Select one correct option for each of the following questions:- 2X10=10 1. (b)

More information

Prepared by Cyrus H. Nozad, MD, University of Tennessee and John Seyerle, MD, Ohio State University

Prepared by Cyrus H. Nozad, MD, University of Tennessee and John Seyerle, MD, Ohio State University Allergy and Immunology Review Corner: Chapter 21 of Middleton s Allergy Principles and Practice, Seventh Edition, edited by N. Franklin Adkinson, et al. Chapter 21: Antigen-Presenting Dendritic Cells (Pages

More information

Chapter 10 (pages ): Differentiation and Functions of CD4+ Effector T Cells Prepared by Kristen Dazy, MD, Scripps Clinic Medical Group

Chapter 10 (pages ): Differentiation and Functions of CD4+ Effector T Cells Prepared by Kristen Dazy, MD, Scripps Clinic Medical Group FIT Board Review Corner September 2015 Welcome to the FIT Board Review Corner, prepared by Andrew Nickels, MD, and Sarah Spriet, DO, senior and junior representatives of ACAAI's Fellows-In-Training (FITs)

More information

Fluid movement in capillaries. Not all fluid is reclaimed at the venous end of the capillaries; that is the job of the lymphatic system

Fluid movement in capillaries. Not all fluid is reclaimed at the venous end of the capillaries; that is the job of the lymphatic system Capillary exchange Fluid movement in capillaries Not all fluid is reclaimed at the venous end of the capillaries; that is the job of the lymphatic system Lymphatic vessels Lymphatic capillaries permeate

More information

Innate Immunity: (I) Molecules & (II) Cells. Part II: Cells (aka the Sentinels)

Innate Immunity: (I) Molecules & (II) Cells. Part II: Cells (aka the Sentinels) Innate Immunity: (I) Molecules & (II) Cells Stephanie Eisenbarth, M.D., Ph.D. FOCIS Advanced Course 2/19/18 Department of Laboratory Medicine Yale School of Medicine Department of Immunobiology Yale School

More information

The Adaptive Immune Response. B-cells

The Adaptive Immune Response. B-cells The Adaptive Immune Response B-cells The innate immune system provides immediate protection. The adaptive response takes time to develop and is antigen specific. Activation of B and T lymphocytes Naive

More information

Adaptive Immunity: Humoral Immune Responses

Adaptive Immunity: Humoral Immune Responses MICR2209 Adaptive Immunity: Humoral Immune Responses Dr Allison Imrie 1 Synopsis: In this lecture we will review the different mechanisms which constitute the humoral immune response, and examine the antibody

More information

INNATE IMMUNITY Non-Specific Immune Response. Physiology Unit 3

INNATE IMMUNITY Non-Specific Immune Response. Physiology Unit 3 INNATE IMMUNITY Non-Specific Immune Response Physiology Unit 3 Protection Against Infection The body has several defenses to protect itself from getting an infection Skin Mucus membranes Serous membranes

More information

I. Lines of Defense Pathogen: Table 1: Types of Immune Mechanisms. Table 2: Innate Immunity: First Lines of Defense

I. Lines of Defense Pathogen: Table 1: Types of Immune Mechanisms. Table 2: Innate Immunity: First Lines of Defense I. Lines of Defense Pathogen: Table 1: Types of Immune Mechanisms Table 2: Innate Immunity: First Lines of Defense Innate Immunity involves nonspecific physical & chemical barriers that are adapted for

More information

The Immune System. These are classified as the Innate and Adaptive Immune Responses. Innate Immunity

The Immune System. These are classified as the Innate and Adaptive Immune Responses. Innate Immunity The Immune System Biological mechanisms that defend an organism must be 1. triggered by a stimulus upon injury or pathogen attack 2. able to counteract the injury or invasion 3. able to recognise foreign

More information

Principles of Adaptive Immunity

Principles of Adaptive Immunity Principles of Adaptive Immunity Chapter 3 Parham Hans de Haard 17 th of May 2010 Agenda Recognition molecules of adaptive immune system Features adaptive immune system Immunoglobulins and T-cell receptors

More information

Structure and Function of Antigen Recognition Molecules

Structure and Function of Antigen Recognition Molecules MICR2209 Structure and Function of Antigen Recognition Molecules Dr Allison Imrie allison.imrie@uwa.edu.au 1 Synopsis: In this lecture we will examine the major receptors used by cells of the innate and

More information

Chapter 24 The Immune System

Chapter 24 The Immune System Chapter 24 The Immune System The Immune System Layered defense system The skin and chemical barriers The innate and adaptive immune systems Immunity The body s ability to recognize and destroy specific

More information

Hematopoiesis. Hematopoiesis. Hematopoiesis

Hematopoiesis. Hematopoiesis. Hematopoiesis Chapter. Cells and Organs of the Immune System Hematopoiesis Hematopoiesis- formation and development of WBC and RBC bone marrow. Hematopoietic stem cell- give rise to any blood cells (constant number,

More information

Chapter 1. Chapter 1 Concepts. MCMP422 Immunology and Biologics Immunology is important personally and professionally!

Chapter 1. Chapter 1 Concepts. MCMP422 Immunology and Biologics Immunology is important personally and professionally! MCMP422 Immunology and Biologics Immunology is important personally and professionally! Learn the language - use the glossary and index RNR - Reading, Note taking, Reviewing All materials in Chapters 1-3

More information

Time course of immune response

Time course of immune response Time course of immune response Route of entry Route of entry (cont.) Steps in infection Barriers to infection Mf receptors Facilitate engulfment Glucan, mannose Scavenger CD11b/CD18 Allows immediate response

More information

Immunology for the Rheumatologist

Immunology for the Rheumatologist Immunology for the Rheumatologist Rheumatologists frequently deal with the immune system gone awry, rarely studying normal immunology. This program is an overview and discussion of the function of the

More information

Determinants of Immunogenicity and Tolerance. Abul K. Abbas, MD Department of Pathology University of California San Francisco

Determinants of Immunogenicity and Tolerance. Abul K. Abbas, MD Department of Pathology University of California San Francisco Determinants of Immunogenicity and Tolerance Abul K. Abbas, MD Department of Pathology University of California San Francisco EIP Symposium Feb 2016 Why do some people respond to therapeutic proteins?

More information

PBS Class #2 Introduction to the Immune System part II Suggested reading: Abbas, pgs , 27-30

PBS Class #2 Introduction to the Immune System part II Suggested reading: Abbas, pgs , 27-30 PBS 803 - Class #2 Introduction to the Immune System part II Suggested reading: Abbas, pgs. 15-25, 27-30 Learning Objectives Compare and contrast the maturation of B and T lymphocytes Compare and contrast

More information

Overview of the Lymphoid System

Overview of the Lymphoid System Overview of the Lymphoid System The Lymphoid System Protects us against disease Lymphoid system cells respond to Environmental pathogens Toxins Abnormal body cells, such as cancers Overview of the Lymphoid

More information

Part III Innate and Adaptive Immune Cells: General Introduction

Part III Innate and Adaptive Immune Cells: General Introduction Innate and Adaptive Immune Cells: General Introduction Iván López-Expósito As an organ specialized in food digestion and nutrient absorption, the intestinal mucosa presents a huge surface area (almost

More information

1. Overview of Adaptive Immunity

1. Overview of Adaptive Immunity Chapter 17A: Adaptive Immunity Part I 1. Overview of Adaptive Immunity 2. T and B Cell Production 3. Antigens & Antigen Presentation 4. Helper T cells 1. Overview of Adaptive Immunity The Nature of Adaptive

More information

Defense mechanism against pathogens

Defense mechanism against pathogens Defense mechanism against pathogens Immune System What is immune system? Cells and organs within an animal s body that contribute to immune defenses against pathogens ( ) Bacteria -Major entry points ;open

More information

Immunology. T-Lymphocytes. 16. Oktober 2014, Ruhr-Universität Bochum Karin Peters,

Immunology. T-Lymphocytes. 16. Oktober 2014, Ruhr-Universität Bochum Karin Peters, Immunology T-Lymphocytes 16. Oktober 2014, Ruhr-Universität Bochum Karin Peters, karin.peters@rub.de The role of T-effector cells in the immune response against microbes cellular immunity humoral immunity

More information

Blood and Immune system Acquired Immunity

Blood and Immune system Acquired Immunity Blood and Immune system Acquired Immunity Immunity Acquired (Adaptive) Immunity Defensive mechanisms include : 1) Innate immunity (Natural or Non specific) 2) Acquired immunity (Adaptive or Specific) Cell-mediated

More information

Immunopathology. 2-Patterned hemodynamic responses, cell surface associated and soluble mediator systems (e.g., complement and coagulation systems).

Immunopathology. 2-Patterned hemodynamic responses, cell surface associated and soluble mediator systems (e.g., complement and coagulation systems). Immunopathology The chief role of the immune system is to protect the host from invasion by foreign agents. Immune responses can be elicited by a wide range of agents including toxins, drugs, chemicals,

More information

Central tolerance. Mechanisms of Immune Tolerance. Regulation of the T cell response

Central tolerance. Mechanisms of Immune Tolerance. Regulation of the T cell response Immunoregulation: A balance between activation and suppression that achieves an efficient immune response without damaging the host. Mechanisms of Immune Tolerance ACTIVATION (immunity) SUPPRESSION (tolerance)

More information

Mechanisms of Immune Tolerance

Mechanisms of Immune Tolerance Immunoregulation: A balance between activation and suppression that achieves an efficient immune response without damaging the host. ACTIVATION (immunity) SUPPRESSION (tolerance) Autoimmunity Immunodeficiency

More information

Immune response. This overview figure summarizes simply how our body responds to foreign molecules that enter to it.

Immune response. This overview figure summarizes simply how our body responds to foreign molecules that enter to it. Immune response This overview figure summarizes simply how our body responds to foreign molecules that enter to it. It s highly recommended to watch Dr Najeeb s lecture that s titled T Helper cells and

More information

Chapter 17. The Lymphatic System and Immunity. Copyright 2010, John Wiley & Sons, Inc.

Chapter 17. The Lymphatic System and Immunity. Copyright 2010, John Wiley & Sons, Inc. Chapter 17 The Lymphatic System and Immunity Immunity Innate Immunity Fast, non-specific and no memory Barriers, ph extremes, Phagocytes & NK cells, fever, inflammation, complement, interferon Adaptive

More information

Innate Immunity. Hathairat Thananchai, DPhil Department of Microbiology Faculty of Medicine Chiang Mai University 2 August 2016

Innate Immunity. Hathairat Thananchai, DPhil Department of Microbiology Faculty of Medicine Chiang Mai University 2 August 2016 Innate Immunity Hathairat Thananchai, DPhil Department of Microbiology Faculty of Medicine Chiang Mai University 2 August 2016 Objectives: Explain how innate immune system recognizes foreign substances

More information

11/25/2017. THE IMMUNE SYSTEM Chapter 43 IMMUNITY INNATE IMMUNITY EXAMPLE IN INSECTS BARRIER DEFENSES INNATE IMMUNITY OF VERTEBRATES

11/25/2017. THE IMMUNE SYSTEM Chapter 43 IMMUNITY INNATE IMMUNITY EXAMPLE IN INSECTS BARRIER DEFENSES INNATE IMMUNITY OF VERTEBRATES THE IMMUNE SYSTEM Chapter 43 IMMUNITY INNATE IMMUNITY EXAMPLE IN INSECTS Exoskeleton made of chitin forms the first barrier to pathogens Digestive system is protected by a chitin-based barrier and lysozyme,

More information

TCR, MHC and coreceptors

TCR, MHC and coreceptors Cooperation In Immune Responses Antigen processing how peptides get into MHC Antigen processing involves the intracellular proteolytic generation of MHC binding proteins Protein antigens may be processed

More information

Basis of Immunology and

Basis of Immunology and Basis of Immunology and Immunophysiopathology of Infectious Diseases Jointly organized by Institut Pasteur in Ho Chi Minh City and Institut Pasteur with kind support from ANRS & Université Pierre et Marie

More information

Origin and functional specializations of DC subsets in the lung

Origin and functional specializations of DC subsets in the lung 2112 Origin and functional specializations of DC subsets in the lung Maud Plantinga 1, Hamida Hammad 1 and Bart N. Lambrecht 1,2 1 Laboratory of Immunoregulation and Mucosal Immunology, Department of Respiratory

More information

Chapter 13: Cytokines

Chapter 13: Cytokines Chapter 13: Cytokines Definition: secreted, low-molecular-weight proteins that regulate the nature, intensity and duration of the immune response by exerting a variety of effects on lymphocytes and/or

More information

Animal Models to Understand Immunity

Animal Models to Understand Immunity Animal Models to Understand Immunity Hussein El Saghire hesaghir@sckcen.be Innate Adaptive immunity Immunity MAPK and NF-kB TLR pathways receptors Fast Slow Non-specific Specific NOD-like receptors T-cell

More information

chapter 17: specific/adaptable defenses of the host: the immune response

chapter 17: specific/adaptable defenses of the host: the immune response chapter 17: specific/adaptable defenses of the host: the immune response defense against infection & illness body defenses innate/ non-specific adaptable/ specific epithelium, fever, inflammation, complement,

More information

The development of T cells in the thymus

The development of T cells in the thymus T cells rearrange their receptors in the thymus whereas B cells do so in the bone marrow. The development of T cells in the thymus The lobular/cellular organization of the thymus Immature cells are called

More information

Immunology Basics Relevant to Cancer Immunotherapy: T Cell Activation, Costimulation, and Effector T Cells

Immunology Basics Relevant to Cancer Immunotherapy: T Cell Activation, Costimulation, and Effector T Cells Immunology Basics Relevant to Cancer Immunotherapy: T Cell Activation, Costimulation, and Effector T Cells Andrew H. Lichtman, M.D. Ph.D. Department of Pathology Brigham and Women s Hospital and Harvard

More information

Campbell's Biology: Concepts and Connections, 7e (Reece et al.) Chapter 24 The Immune System Multiple-Choice Questions

Campbell's Biology: Concepts and Connections, 7e (Reece et al.) Chapter 24 The Immune System Multiple-Choice Questions Campbell's Biology: Concepts and Connections, 7e (Reece et al.) Chapter 24 The Immune System 24.1 Multiple-Choice Questions 1) The body's innate defenses against infection include A) several nonspecific

More information

LESSON 2: THE ADAPTIVE IMMUNITY

LESSON 2: THE ADAPTIVE IMMUNITY Introduction to immunology. LESSON 2: THE ADAPTIVE IMMUNITY Today we will get to know: The adaptive immunity T- and B-cells Antigens and their recognition How T-cells work 1 The adaptive immunity Unlike

More information

Allergy and Immunology Review Corner: Chapter 13 of Immunology IV: Clinical Applications in Health and Disease, by Joseph A. Bellanti, MD.

Allergy and Immunology Review Corner: Chapter 13 of Immunology IV: Clinical Applications in Health and Disease, by Joseph A. Bellanti, MD. Allergy and Immunology Review Corner: Chapter 13 of Immunology IV: Clinical Applications in Health and Disease, by Joseph A. Bellanti, MD. Chapter 13: Mechanisms of Immunity to Viral Disease Prepared by

More information

General Biology. A summary of innate and acquired immunity. 11. The Immune System. Repetition. The Lymphatic System. Course No: BNG2003 Credits: 3.

General Biology. A summary of innate and acquired immunity. 11. The Immune System. Repetition. The Lymphatic System. Course No: BNG2003 Credits: 3. A summary of innate and acquired immunity General iology INNATE IMMUNITY Rapid responses to a broad range of microbes Course No: NG00 Credits:.00 External defenses Invading microbes (pathogens). The Immune

More information

T cell maturation. T-cell Maturation. What allows T cell maturation?

T cell maturation. T-cell Maturation. What allows T cell maturation? T-cell Maturation What allows T cell maturation? Direct contact with thymic epithelial cells Influence of thymic hormones Growth factors (cytokines, CSF) T cell maturation T cell progenitor DN DP SP 2ry

More information

Lecture outline. Immunological tolerance and immune regulation. Central and peripheral tolerance. Inhibitory receptors of T cells. Regulatory T cells

Lecture outline. Immunological tolerance and immune regulation. Central and peripheral tolerance. Inhibitory receptors of T cells. Regulatory T cells 1 Immunological tolerance and immune regulation Abul K. Abbas UCSF 2 Lecture outline Central and peripheral tolerance Inhibitory receptors of T cells Regulatory T cells 1 The immunological equilibrium:

More information

T Cell Activation, Costimulation and Regulation

T Cell Activation, Costimulation and Regulation 1 T Cell Activation, Costimulation and Regulation Abul K. Abbas, MD University of California San Francisco 2 Lecture outline T cell antigen recognition and activation Costimulation, the B7:CD28 family

More information

Overview. Barriers help animals defend against many dangerous pathogens they encounter.

Overview. Barriers help animals defend against many dangerous pathogens they encounter. Immunity Overview Barriers help animals defend against many dangerous pathogens they encounter. The immune system recognizes foreign bodies and responds with the production of immune cells and proteins.

More information

Long-term innate immune memory via effects on bone marrow progenitors

Long-term innate immune memory via effects on bone marrow progenitors Long-term innate immune memory via effects on bone marrow progenitors Helen S Goodridge, PhD helen.goodridge@csmc.edu Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, USA Fondation

More information

Introduction to Immunopathology

Introduction to Immunopathology MICR2209 Introduction to Immunopathology Dr Allison Imrie 1 Allergy and Hypersensitivity Adaptive immune responses can sometimes be elicited by antigens not associated with infectious agents, and this

More information

Immunology. Anas Abu-Humaidan M.D. Ph.D. Transplant immunology+ Secondary immune deficiency

Immunology. Anas Abu-Humaidan M.D. Ph.D. Transplant immunology+ Secondary immune deficiency Immunology Anas Abu-Humaidan M.D. Ph.D. Transplant immunology+ Secondary immune deficiency Transplant Immunology Transplantation is the process of moving cells, tissues or organs from one site to another

More information

Immune response to infection

Immune response to infection Immune response to infection Dr. Sandra Nitsche (Sandra.Nitsche@rub.de ) 20.06.2018 1 Course of acute infection Typical acute infection that is cleared by an adaptive immune reaction 1. invasion of pathogen

More information

WHY IS THIS IMPORTANT?

WHY IS THIS IMPORTANT? CHAPTER 16 THE ADAPTIVE IMMUNE RESPONSE WHY IS THIS IMPORTANT? The adaptive immune system protects us from many infections The adaptive immune system has memory so we are not infected by the same pathogen

More information

5/1/13. The proportion of thymus that produces T cells decreases with age. The cellular organization of the thymus

5/1/13. The proportion of thymus that produces T cells decreases with age. The cellular organization of the thymus T cell precursors migrate from the bone marrow via the blood to the thymus to mature 1 2 The cellular organization of the thymus The proportion of thymus that produces T cells decreases with age 3 4 1

More information

1. The barriers of the innate immune system to infection

1. The barriers of the innate immune system to infection Section 3.qxd 16/06/05 2:11 PM Page 12 12 SECTION THREE: Fleshed out 1. The barriers of the innate immune system to infection Questions What are the three characteristics of the innate immune system? What

More information

Cytokines (II) Dr. Aws Alshamsan Department of Pharmaceu5cs Office: AA87 Tel:

Cytokines (II) Dr. Aws Alshamsan Department of Pharmaceu5cs Office: AA87 Tel: Cytokines (II) Dr. Aws Alshamsan Department of Pharmaceu5cs Office: AA87 Tel: 4677363 aalshamsan@ksu.edu.sa Learning Objectives By the end of this lecture you will be able to: 1 Understand the physiological

More information

The Skinny of the Immune System

The Skinny of the Immune System The Skinny of the Immune System Robert Hostoffer, DO, FACOP, FAAP Associate Professor of Pediatrics Case Western Reserve University, Cleveland, Ohio Overview 1. Immune system of the skin 2. Immune Players

More information

SEVENTH EDITION CHAPTER

SEVENTH EDITION CHAPTER Judy Owen Jenni Punt Sharon Stranford Kuby Immunology SEVENTH EDITION CHAPTER 16 Tolerance, Autoimmunity, and Transplantation Copyright 2013 by W. H. Freeman and Company Immune tolerance: history * Some

More information

7/6/2009. The study of the immune system and of diseases that occur as a result of inappropriate or inadequate actions of the immune system.

7/6/2009. The study of the immune system and of diseases that occur as a result of inappropriate or inadequate actions of the immune system. Diseases of Immunity 2009 CL Davis General Pathology Paul W. Snyder, DVM, PhD Purdue University Acknowledgements Pathologic Basis of Veterinary Disease, 4 th Ed Veterinary Immunology, An Introduction 8

More information

Lifeblood Lab Activity

Lifeblood Lab Activity History of Blood: It is the universal symbol of horror, of death, yet it is the one thing that keeps you living. It is the blood that is coursing through your veins. But, what do you really know about

More information

CELL BIOLOGY - CLUTCH CH THE IMMUNE SYSTEM.

CELL BIOLOGY - CLUTCH CH THE IMMUNE SYSTEM. !! www.clutchprep.com CONCEPT: OVERVIEW OF HOST DEFENSES The human body contains three lines of against infectious agents (pathogens) 1. Mechanical and chemical boundaries (part of the innate immune system)

More information

T Cell Effector Mechanisms I: B cell Help & DTH

T Cell Effector Mechanisms I: B cell Help & DTH T Cell Effector Mechanisms I: B cell Help & DTH Ned Braunstein, MD The Major T Cell Subsets p56 lck + T cells γ δ ε ζ ζ p56 lck CD8+ T cells γ δ ε ζ ζ Cα Cβ Vα Vβ CD3 CD8 Cα Cβ Vα Vβ CD3 MHC II peptide

More information

Immunology lecture: 14. Cytokines: Main source: Fibroblast, but actually it can be produced by other types of cells

Immunology lecture: 14. Cytokines: Main source: Fibroblast, but actually it can be produced by other types of cells Immunology lecture: 14 Cytokines: 1)Interferons"IFN" : 2 types Type 1 : IFN-Alpha : Main source: Macrophages IFN-Beta: Main source: Fibroblast, but actually it can be produced by other types of cells **There

More information

The Adaptive Immune Response: T lymphocytes and Their Functional Types *

The Adaptive Immune Response: T lymphocytes and Their Functional Types * OpenStax-CNX module: m46560 1 The Adaptive Immune Response: T lymphocytes and Their Functional Types * OpenStax This work is produced by OpenStax-CNX and licensed under the Creative Commons Attribution

More information

The Innate Immune Response

The Innate Immune Response The Innate Immune Response FUNCTIONS OF THE IMMUNE SYSTEM: Recognize, destroy and clear a diversity of pathogens. Initiate tissue and wound healing processes. Recognize and clear damaged self components.

More information

HISTO-PHYSIOLOGY HISTO-PHYSIOLOGY HISTO-PHYSIOLOGY. 09-Mar-15. Dr. Muhammad Tariq Javed. RESPIRATORY SYSTEM Lec-1

HISTO-PHYSIOLOGY HISTO-PHYSIOLOGY HISTO-PHYSIOLOGY. 09-Mar-15. Dr. Muhammad Tariq Javed. RESPIRATORY SYSTEM Lec-1 RESPIRATORY SYSTEM Lec-1 Dr. Muhammad Tariq Javed Professor Department of Pathology, University of Agriculture, Faisalabad. Email: mtjaved@uaf.edu.pk Web: http://www.geocities.ws/mtjaved 1 2 Conducting

More information

Immune System AP SBI4UP

Immune System AP SBI4UP Immune System AP SBI4UP TYPES OF IMMUNITY INNATE IMMUNITY ACQUIRED IMMUNITY EXTERNAL DEFENCES INTERNAL DEFENCES HUMORAL RESPONSE Skin Phagocytic Cells CELL- MEDIATED RESPONSE Mucus layer Antimicrobial

More information

Scott Abrams, Ph.D. Professor of Oncology, x4375 Kuby Immunology SEVENTH EDITION

Scott Abrams, Ph.D. Professor of Oncology, x4375 Kuby Immunology SEVENTH EDITION Scott Abrams, Ph.D. Professor of Oncology, x4375 scott.abrams@roswellpark.org Kuby Immunology SEVENTH EDITION CHAPTER 13 Effector Responses: Cell- and Antibody-Mediated Immunity Copyright 2013 by W. H.

More information

T Cell Activation. Patricia Fitzgerald-Bocarsly March 18, 2009

T Cell Activation. Patricia Fitzgerald-Bocarsly March 18, 2009 T Cell Activation Patricia Fitzgerald-Bocarsly March 18, 2009 Phases of Adaptive Immune Responses Phases of T cell responses IL-2 acts as an autocrine growth factor Fig. 11-11 Clonal Expansion of T cells

More information

CYTOKINE RECEPTORS AND SIGNAL TRANSDUCTION

CYTOKINE RECEPTORS AND SIGNAL TRANSDUCTION CYTOKINE RECEPTORS AND SIGNAL TRANSDUCTION What is Cytokine? Secreted popypeptide (protein) involved in cell-to-cell signaling. Acts in paracrine or autocrine fashion through specific cellular receptors.

More information

JPEMS Nantes, Basic Immunology INNATE IMMUNITY

JPEMS Nantes, Basic Immunology INNATE IMMUNITY JPEMS Nantes, 2014- Basic Immunology INNATE IMMUNITY Teacher: Pr. Régis Josien, Laboratoire d Immunologie and INSERM U1064, CHU Nantes Regis.Josien@univ-nantes.fr 1 Contents 1. General features and specificity

More information

Clinical Basis of the Immune Response and the Complement Cascade

Clinical Basis of the Immune Response and the Complement Cascade Clinical Basis of the Immune Response and the Complement Cascade Bryan L. Martin, DO, MMAS, FACAAI, FAAAAI, FACOI, FACP Emeritus Professor of Medicine and Pediatrics President, American College of Allergy,

More information

The Immune System All animals have innate immunity, a defense active immediately

The Immune System All animals have innate immunity, a defense active immediately The Immune System All animals have innate immunity, a defense active immediately upon infection Vertebrates also have adaptive immunity Figure 43.2 INNATE IMMUNITY (all animals) Recognition of traits shared

More information

General information. Cell mediated immunity. 455 LSA, Tuesday 11 to noon. Anytime after class.

General information. Cell mediated immunity. 455 LSA, Tuesday 11 to noon. Anytime after class. General information Cell mediated immunity 455 LSA, Tuesday 11 to noon Anytime after class T-cell precursors Thymus Naive T-cells (CD8 or CD4) email: lcoscoy@berkeley.edu edu Use MCB150 as subject line

More information

The Immune System: Innate and Adaptive Body Defenses Outline PART 1: INNATE DEFENSES 21.1 Surface barriers act as the first line of defense to keep

The Immune System: Innate and Adaptive Body Defenses Outline PART 1: INNATE DEFENSES 21.1 Surface barriers act as the first line of defense to keep The Immune System: Innate and Adaptive Body Defenses Outline PART 1: INNATE DEFENSES 21.1 Surface barriers act as the first line of defense to keep invaders out of the body (pp. 772 773; Fig. 21.1; Table

More information

Properties & Overview of IRs Dr. Nasser M. Kaplan JUST, Jordan. 10-Jul-16 NM Kaplan 1

Properties & Overview of IRs Dr. Nasser M. Kaplan JUST, Jordan. 10-Jul-16 NM Kaplan 1 Properties & Overview of IRs Dr. Nasser M. Kaplan JUST, Jordan 10-Jul-16 NM Kaplan 1 Major components of IS & their properties Definitions IS = cells & molecules responsible for: 1- Physiologic; protective

More information

Subject Index. Bcl-2, apoptosis regulation Bone marrow, polymorphonuclear neutrophil release 24, 26

Subject Index. Bcl-2, apoptosis regulation Bone marrow, polymorphonuclear neutrophil release 24, 26 Subject Index A1, apoptosis regulation 217, 218 Adaptive immunity, polymorphonuclear neutrophil role 31 33 Angiogenesis cancer 178 endometrium remodeling 172 HIV Tat induction mechanism 176 inflammatory

More information

Components of the innate immune system

Components of the innate immune system Components of the innate immune system Before our discussion about innate immunity Differences between innate and adaptive systems: Innate immune system = natural = native -Germline: prepared before exposure

More information

Immunology of Asthma. Kenneth J. Goodrum,Ph. Ph.D. Ohio University College of Osteopathic Medicine

Immunology of Asthma. Kenneth J. Goodrum,Ph. Ph.D. Ohio University College of Osteopathic Medicine Immunology of Asthma Kenneth J. Goodrum,Ph Ph.D. Ohio University College of Osteopathic Medicine Outline Consensus characteristics/incidence data Immune/inflammatory basis Etiology/Genetic basis Hygiene

More information