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 2a. expansion of pathogen 2b. reaches threshold activation of adaptive immune mechanisms 2c. Reaction of innate immune system 2d. Memory response is started 3. 4-7d adaptive immune reaction (e.g. effector t- cells, antibodies) eliminate the infection 4a. antigen amount under threshold 4b. Immune reaction stops 4c. Immunological memory response protects often long lasting against new infection with same pathogen 2
Protection against infection stages of infection 1. Attachment on epithelial cells and infection 2. local, innate immune reaction dampen the infection 3. expansion of microorganism to lymphatic system 4. adaptiv immune response eliminate the pathogen 3
Time course of infection in normal/immunodeficient indiviuum Duration of infection in immunocompromised and healthy mice/humans is depended on the immune status. Red: without innate immune reaction Green: with innate but without adaptive immunity Yellow: immunocompetent mice/human Mac: macrophages PMN: polymorphonuclear leukocytes T: T-cells B: B-cells 4
Balance of T-cell development by cytokines produced by DCs T H 17: T-helper cells Typ 17 -> high TGF-ß, low IL-6 and IL-23 T reg : regulatory T-helper cells -> high TGF-ß, high IL-6 and IL-23 Early infection phase triggers differentiation from naïve CD4- cells to T H 17 cells and not to T reg IL-17 and IL-17F were produced by T H 17 cells to induce chemokine production in e.g. epithelial cells for recruitment of neutrophils to the side of infection Cells without antigen contact stay naive 5
T cell differentiation influenced by cytokines Viral infection (and some intracellular bacterial infections) triggers DC s (production of IL-12) and NK cells (production of IFN-γ) which both cause T H 1 -> IFN-γ IL-2 TNF-β IL-4 produced by NK-T-cells or other cells triggered by helminth or other pathogens cause T H 2 profile of the naïve CD4-T-cell -> IL-4 IL-5 IL-13 6
T cells produce cytokines for regulation of other subsets T reg produce TGF-β which dampen the differentiation to T H 1, T H 2 or T H 17 In case of an infection: DC s produce IL-6 -> T H 17 upregulated and T reg is depressed (TGF-β down) T H 1 or T H 2 cytokine (IL-10; IFN-γ) dampens T H 17 and regulation of subsets by downregulation of the other subset of helper T cells 7
Infection may trigger T H 1 polarization via TLR-pathways - Infection may trigger to a T H 1-polarisation via signaling pathways by Toll-like receptors - Adaptor protein MyD88 is a central component by signal transduction of toll-like receptors - KO-mice could not respond to T.gondii with IL-12, IFN-γ and T H 1 reaction profile so they died 2 weeks after infection 8
Manipulating the CD4 T-cell subsets by cytokines in early stages of infection Cytokine milieu is responsible for the development of naïve T cells to differentiate into T H 1(IL-4, Il-5, IL13) or T H 2 (IFN-γ, IL-2, TNF-β) cells Influence by blocking antibodies (cytokines or receptors) 9
Change of surface molecules on effector T cells Effector T cells change their surface molecules for binding on endothelial cells in the lymph node L-Selectin in naïve T cells binds to CD34 After differentiation in the lymph node integrine VLA-4 and LFA-1 are upregulated and bind to VCAM-1 or ICAM-1 respectively on endothelial cells CD45RO fasten the specific antigen stimulation up 10
Usage of chemokines for migration Lymphocytes which are at the dermis binds to E-Selectin (via CLA) and CCL17 (via CCR4) in the endothelium Lymphocyte at the cell surface (ceratinocyt) binds via CCL27 to CCR10 as receptor 11
Cytokines IL-12 and IL-23 share subunits - Both cytokines augment the activity and proliferation of the CD4 subsets that express receptors for them - T H 1-cells express IL-12R - T H 17-cells express IL-23R - Mice deficient in p40 lack expression of both of there cytokines and show an immune deficiencies in both T H 1- and T H 17 activity 12
CD8 T cell activation by APCs Activated DC s during infection express B7 and other costimulatory molecules and activate naïve CD8-T cells and via Peptid-MHC-I-complex for proliferation of the Cytotoxic-Tlymphocyte (CTL) (left) Activated DC s also produce IL-12 and IL-18 and stimulate naïve CD8-t cells to produce IFN-γ IFN-γ activates macrophages to eliminate intracellular bacterial or helps other cell types for an antiviral reaction 14
Antigen specific T and B- cells can interact at the peripheral lymphatic tissue 15
Different strategies to clear primary infection 16
Protective immunity (immunological memory) After first infection with the pathogen where are pathogen specific antibodies and effector-t cells are generated the immunity based on immunological memory response to secondary infection reacts immediately (often without any symptoms of infection) 17
https://youtu.be/zqgocoubi6s Das Immunsystem erklärt - Bakterien Infektion Kurzgesagt In a Nutshell 18