Immunology 2011 Lecture 14 Cell Interactions in CMI II 7 October

Transcription

1 Immunology 2011 Lecture 1 Cell Interactions in CMI October OUTLINE Cell Interactions in CMI Cell Mediated Killing (x3) MHC Restricted Recognition Cell interactions (3): APC/TH1, TH1/TC, TC/Target Immunoglobulin Superfamily Antigen processing Superantigens/Toxic Shock model of resistance Killing, TH1/TH2 regulation SOME MEMBERS OF THE IMMUNOGLOBULIN SUPERFAMILY C L V L L C HI C H C HI VH H Vα Cα α β Vβ Cβ Ig TcR Class Class I MHC There are many others, including many receptors and adhesion molecules. α β Many cell adhesion molecules (NCAMs, ICAMs, VCAMs etc.), Fc and cytokine receptors, and others m α α3 SCHEMATIC STRUCTURE OF MHC CLASS V L C L Ag V H C H1 C H2 cell membrane cell membrane Without peptide (not present in nature) With antigen peptide C H3 Mouse IgG (McPherson, 19) 1

2 Human MHC Class I α-chain and β-2m MHC Class α and β chains α3 β 2m Class I, top view Empty peptide-binding groove Class, top view Empty peptide-binding groove Class, top view Occupied groove 2

3 SOME MEMBERS OF THE IMMUNOGLOBULIN SUPERFAMILY L V L H C L VH C HI α β α β α exogenous peptide endogenous peptide Exogenous protein phagocytosis or pinocytosis Class vesicle lysosome fusion exocytosis MHC Class presentation C H Vα Vβ C HI Cα Cβ m α3 Ig TcR Class Class I Endogenous protein proteasome TAP Class I in ER Golgi/exocytosis MHC Class I presentation MHC There are many others, including many receptors and adhesion molecules. Class α & β chain Class I α-chain + m SEPARATE INTRACELLULAR PATHWAYS FOR CLASS I AND CLASS PRESENTATION OF PEPTIDES The general rule is: Endogenous Class I Exogenous Class However Endogenous peptides may be released, endocytosed & presented in Class (not surprisingly) Three distinct forms of endocytosis Phagocytosis e.g. MФ, DC, PMN Pinocytosis all cells Receptor-mediated endocytosis e.g. B-cell All can lead to Class presentation pathway. Infected cell targeted Non- cell also targeted Dendritic cells may take up exogenous peptides and direct them to their own Class I pathway ( Cross-Priming - additional help for Tc development) Cross-presentation by peptide transfer through gap junctions. Neijssen et al. (2005) Nature 3:3-3

4 "ASSOCIATED RECOGNITION" IN CELL-MEDIATED IMMUNITY ANTIGEN PRESENTING CELL VIRUS-INFECTED CELL T D (T ) TH2 TH1 H1 activation of macrophages: IFN-γ, MIF/MCF, etc. = viral antigen = CD Killer TC cells = CDare CD+ triggering: Class restricted Only professional APCs can initiate T-cell killing and other CMI potentially dangerous = B/CD2 2 = MHC Class I lunatics, they must = MHC Class be = TcR kept under tight = IL-2 recep. civilian control. = proliferation. Death IL-, etc. (B-cell) Free Virus Stimulation phase IL-2 T TC C cells recognize only cellbound Ag, don t waste Effector resources phase trying to do Abs job no recognition Recognition I "killer" CD+ triggering: Class I restricted "precursor" CD+ killing: Class I restricted Toxic Shock Syndrome A 35-year-old man was admitted to hospital with a - day history of high fever, sore throat and a diffuse erythematous rash over the anterior chest wall. Additional findings on examination included hypotension (blood pressure 0/50mmHg), conjunctival injection, and cellulitis of both calves. Over the next 2h there was increasing pain and swelling of the right calf associated with disappearance of the pedal pulse, necessitating emergency fasciotomies of the anterolateral and posterior compartments of the right leg. Gram stain of the fluid obtained during fasciotomy showed gram-positive cocci with an abundant growth of Group A β-hemolytic streptococci on muscle culture. The same organism was also isolated from throat and blood cultures. Exotoxin typing revealed pyrogenic exotoxins A and B. A diagnosis of streptococcal toxic shock syndrome was made on the basis of the above findings. The patient made a full recovery following treatment with intravenous clindamycin. Question: What is the molecular basis for these symptoms? 2 APC weak binding, no signalling TH no specific TcR/Ag recognition 2 APC TH TSST-1 strong binding, signalling IL-2, TNFα... TSST-1 AS "SUPERANTIGEN" Cross-links TCR and MHC Class. Massive activation of CD+ T-cells and release of cytokines; Cytokine Storm normal immune response: ~1/10,000 T-cells superantigen : ~1-20% of all T-cells Bacterial and viral superantigens cause massive non-specific triggering of T-cells Toxic Shock Syndrome Toxin (TSST-1, -2) [Strep] Streptococcal Pyogenic Exotoxin A (SPEA) Staphylococcal Enterotoxins B & C3 (SEB, SEC-3) Mycoplasma arthritidis-derived superantigen (MAS) Exfoliative toxin A (ETA) [Staph] Note: superantigens are not really antigens... "ASSOCIATED RECOGNITION" IN CELL-MEDIATED IMMUNITY ANTIGEN PRESENTING CELL VIRUS-INFECTED CELL T cell responses have both specific and non-specific consequences MΦ & PMNs T D (T ) TH2 TH1 H1 activation of macrophages: IFN-γ, MIF/MCF, etc. = viral antigen are non-specific... = CD = CD inflammation, DTH... = B/CD2 2 = MHC Class I = MHC Class = TcR = IL-2 recep. = proliferation. Death IL-, etc. (B-cell) Free Virus IL-2 no recognition Effector phase Recognition I Stimulation phase "killer" "precursor" induction is Ag-specific TC killing is Ag-specific

5 Pathogen Adaptive response Extracellular bacteria Viruses Intracellular bacteria HI: Antibodies (immobilization, opsonization, C-dependent lysis ) CMI: TC-mediated killing (MHC Class I with viral peptides )??? CMI against infection by Intracellular Bacteria TRANSFER: serum macrophages lymphocytes Immunize with CHALLENGE RECIPIENTS WITH: Mycobacteria + Mycobacteria immune immune = CMI specific IMMUNITY TO LISTERIA IS CELL-MEDIATED live killed Infect with IL-12 T H1 Sensitized T-cell Macrophage with live IFN-γ T-CELLS ACTIVATE MACROPHAGES TO KILL LISTERIA "Activated" macrophage; killed TRANSFER: serum macrophages lymphocytes Immunize with CHALLENGE RECIPIENTS WITH: Mycobacteria + Mycobacteria no transfer with MΦ activation short-lived immune immune IMMUNITY TO LISTERIA IS CELL-MEDIATED Induction of immunity is specific Effector function is non-specific Roles of CD+ T-cells ( which recognize MHC Class -bound peptides) Help B-cells become Ab-secreting cells Help CD+ T-cells become killer cells Activate macrophages to kill intracellular bacteria What are the consequences of Class deficiency? Bare Lymphocyte Syndrome (199) Absence of MHC Class (="type 2") Repeated, severe infections - bacterial, viral, fungal, protozoal, respiratory, diarrhea, failure to thrive (presents like SCID) Inheritance: varied autosomal recessive, symptoms begin to appear in early infancy Deficiency or absence of MHC Class expression CD+ T-cell lymphopenia [why??] Hypogammaglobulinemia (IgG, IgM, IgA) Deficient or absent antibody responses (immunizations, microbial antigens) Therapy: Hemopoietic Stem Cell transplant Deficiency in T-cell help for B-cells and CD+ T cells, for macrophage activation, etc. 5

6 Modes of Immune destruction of target cells Tc Tc cell recognizes target antigen cell binds to target cell MΦ Ab binds to target antigen TC ADCC Tc Target cell killed Target cell killed PMN Effector cells bind Target cell killed via Fc receptors Innate Immunity Mechanism of -Recognition (CHO stimulates) Upregulation (or structural variation) of CHO + KIR CHO-R CHO I - KILL? Target (Class I inhibits) Change in either can trigger killing Downregulation of Class I WEDNESDAY Thymus & Humoral Immunity, Chap 13, A12 Cell Markers & T/B Interactions, Chaps. 1, 15 THURSDAY Lymphoid Tissue Architecture, Chap. 16 FRIDAY POPS I, Jaundiced Baby 10:00 AM in Med Surge multipurpose lab (mandatory participation) 6