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Activated T -cell

a. a. APC. APC. APC. APC. APC. APC. CD8 TCR. CD8 TCR. CD8 TCR. CD4 TCR. CD4 TCR. CD4 TCR. Ag. Ag. Ag. T-CELL DIFFERENTIATION IN THE PERIPHERY. Memory T-cell. Activated T -cell. M ature naive T-cell.

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Activated T -cell

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  1. a a APC APC APC APC APC APC CD8TCR CD8TCR CD8TCR CD4 TCR CD4 TCR CD4 TCR Ag Ag Ag T-CELL DIFFERENTIATION IN THE PERIPHERY Memory T-cell Activated T-cell Mature naiveT-cell Naiveor „resting” T cells… restlessmigration and recirculation, LN, lymph, blood…forseveralmonth, which is theirlifespan

  2. PERIPHERAL TOLERANCE IMMUNE RESPONSES ARE NOT INITIATED IN THE PERIPHERY Normal tissue cells do not express MHC class II NO SIGNAL 1. for CD4+ Th activation Normal tissue cells do not express co-stimulatory molecules and do not produce T cell differentiating cytokines NO SIGNAL 2. for CD4+ Th activation Migration of naive T lymphocytes to normal tissues is limited Antigen presenting cells are not activated in normal tissues NO SIGNAL 3. for CD4+ Th activation PERIPHERAL TISSUES TOLERIZE THEMSELVES

  3. T-CELL DIFFERENTIATION Environmentalfactors and interactionswithAPCs initiatedistinctdifferentiationprogramsin naiveT-cells

  4. Clonal selection and differentiation IL-2 T APC How can this cell give help to or kill cells that express low levels of B7 family costimulators? Effector T cell Arming of effector T cells Activation of NAÏVE T cells by signal 1 and 2 is not sufficient to trigger effector function, but….. the T cell will be activated to proliferate and differentiate under the control of autocrine IL-2 to an effector T cell. These T cells are ARMED

  5. Naïve T cell IL-2 Armed Effector T cell Armed Effector T cell CD28 TcR Co-receptor Kill Epithelial cell Epithelial cell Epithelial cell Effector function or Anergy? This contrasts the situation with naïve T cells, which are anergised without costimulation Clonally selected, proliferating and differentiated T cell sees antigen on a B7 negative epithelial cell The effector programme of the T cell is activated without costimulation

  6. Virus, bacteria, protozoa, fungi CD8+ cytotoxic T cell NK cell DCMΦ IL-12 IL-12 IFNγ IFNγ IL-12 Th1 Th0 Th2 IL-2 IFNγ TNF-β GM-CSF IL-3 IL-4 IL-5 IL-10 IL-13 IL-12 FAVORS POLARIZATION TO TH1-TYPE EFFECTOR T-CELLS

  7. Self tissue, tumor cell Macrophage DC IL-10 IL-10 Th1 Th0 Th2 IL-2 IFNγ TNF-β TNF-α GM-CSF IL-3 IL-4 IL-5 IL-10 IL-13 IL-10 FAVORS POLARIZATION TO Th2 TOLERANCE

  8. POLARIZATION OF HELPER T LYMPHOCYTES IS DIRECTED BY DENDRITIC CELL-DERIVED AND AUTOCRINE CYTOKINES AND TRANSCRIPTION FACTORS

  9. EFFECTOR FUNCTIONS OF TH1 CELLS Activation Killing Proliferation Feed back Entry to tissue Recruitment

  10. Granulomas develop when intracellular pathogens resist elimination Long term persistance of infectious agent in a separated envitonment

  11. Responses to Mycobacterium leprae are sharply differentiated in tuberculoid and lepromatous leprosy.

  12. Th2 Th1 Th0 Inflammatory cytokines CELLULAR IMMUNE RESPONSE Anti-inflammatory cytokines HUMORAL IMMUNE RESPONSE IL-4, IL-5, IL-10 IFNγ, IL-2, TNF-β/LT EFFECTOR CD4+ HELPER T LYMPHOCYTES SECRETE DIFFERENT CYTOKINES IFNγ IL-4

  13. SUBSETS OF HELPER T LYMPHOCYTES COLLABORATE WITH DIFFERENT PROFESSIONAL ANTIGEN PRESENTING CELLS Th2 B IL - 4 B7 expression  antigen presentation Germinal center formation Affinity maturation Isotype switch Memory B cell generation CD40L CD40 B7 expression  antigen presentation MHC-II expression  antigen presentation Mature dendritic cell Activated macrophage CD40L CD40 DCMΦ Th1 IFNγ

  14. Th1 Intracellularpathogens Inflammation Tcactivation IgG1 & IgG3antibodies ADCC, opsonisation Complementactivation CD4 TCR Th2 Extracellularpathogens Multicellularparasites SecretoryIgA IgE, allergy CD4 DC TCR CD4 Th17 Extracellularpathogen Inflammation Autoimmunediseases Allergy TCR CD4 TCR Th0 blast Treg Th1 inhibition Maintenance of immunologicaltolerance CD4 TCR CLONAL EXPANSION DIFFERENTIATION EPIGENETIC CHANGES, MEMORY EFFECTOR HELPER T-CELLS Naive CD4+ T cell CD4 TCR INTERACTION ACTIVATION INSTRUCTION

  15. CHARACTERISTICS OF EFFECTOR HELPER T LYMPHOCYTES CCR1 CCR5 CXCR3 CCR6 T-bet GATA3 RORγt FoxP3 Th17 Th1 CD45RBlo IL-23R IL-12Rα LAG3 CD25 IL-2Rα CD127 IL-7Rα↓ CCR4 CCR3 CXCR4 Th2 Treg CD45RBhigh IL-1R CD30 CTLA4 B7 ligand GITR TCR+ CD4+ CD28+ CD25+

  16. IL-2Rγ PU.1 & IRF4 Th9 Th9 IL-4Rα Th0 HOWEVER, THIS IS NOT THE END OF THE STORY… AS OF YET… CHARACTERISTICS OF EFFECTOR HELPER T LYMPHOCYTES – Th9 CELLS TCR+ CD4+ CD28+ CD25+ Parasitichelminthinfections Chronicallergicinflammation Asthma Autoimmunediseases TGF-β IL-4 IL-9 IL-10 CCL17 CCL22 Othercytokinesthatenhance Th9 polarization: Type I IFNs, IL-1β, IL-6

  17. Annunziato and Romagnani (2009)Arthritis Research & Therapy11:257

  18. Th2 functions

  19. Th2 cellsstimulatetheproliferation and differentiation of naive B cells

  20. ISOTYPE SWITCH IN ACTIVATED B CELLS IS REGULATED BY HELPER T CELL - DERIVED CYTOKINES • ISOTYPE SWITCH IS INFLUENCED BY • site of antigen entry • tissue microenvironment • nature of professional antigen presenting cells • polarization of helper T lymphocytes

  21. IL-2 IL-4 IL-5 Helper T cell IgM IL-2 IL-4 IL-6 IFNγ IL-2 IL-4 IL-5 IgG IL-5 TGFβ IgA B cell IL-4 IgE REGULATION OF ISOTYPE SWITCH OF B CELLS B cell proliferation and differentiation – isotype switch

  22. Human Ig classes and subclasses Complementactivation ClassicalFcRbinding IgM ++++- IgG1 +++++++ IgG2 ++ IgG3 +++++++ IgG4 +/-+ IgA -+++ IgE -+++ IgD --

  23. Cytotoxic T-cells

  24. PRIMING OF CD8+ CYTOTOXIC T CELLS

  25. PRIMING OF CD8+ CYTOTOXIC T CELLS THROUGH COLLABORATION OF HELPER AND CYTOTOXIC T-CELLS ACTIVATION CD4+ Th CD40L IL-2 B7 CD28 CD8+ Tc • Dendritic cells with high B7 expression activate CD8+ T cells directly • Dendritic cells activate CD4+ T cells, which in turn enhance the co-stimulatory activity of dendritic cells • Activated CD4+ T cells secrete cytokines (IL-2), which directly acts on activated CD8+ T cell

  26. KILLING OF INFECTED CELLS BY CTL Recognition by CTLs induces secretion of cytotoxins to the target cell

  27. PHYSIOLOGICAL AND PATHOLOGIC CELL DEATH Apoptotic signal Cell demage

  28. Healthy cell Necrotic cell Late apoptotic cell Apoptotic cell APOPTOSIS AND NECROSIS • HIGHLY REGULATED PROCESS • Induction • Excecution • Mitochondrialfunction * Activation of caspases • Electrontransport * Serineprotease,calpain, proteasome • Oxidativephosphorylateion * Redoxpotential • ATP synthesis *DNA degradation (endonuclease)

  29. MECHANISM OF CELLULAR KILLING BY CD8+ CYTOTOXIC T LYMPHOCYTES Proteoglycans H2O, Ca++, ions Polymerized perforin Granzyme APOPTOSIS CYTOKINE RELEASE CD8+ T CELL TARGET CELL

  30. TNF AND TNF RECEPTOR FAMILY MEMBERS AND THEIR LIGANDS Soluble TNF TNF-α TNF-β/LTα TNFRI TNFRII RECEPTOR TRIMERIZATION LTβ LTα LTβ LTβR Soluble FasL FasL FAS CD40L CD30L CD27L 4-1BBL Ox40L CD40 CD30 CD27 4-1BB Ox40 DEATH DOMAIN

  31. MECHANISMS OF FAS RECEPTOR – MEDIATED PROGRAMED CELL DEATH

  32. CONSEQUENCE OF T CELL-MEDIATED IMMUNE RESPONSES Cytotoxic T lymphocytes recognize virus-infected or tumor cells Activated cytotoxic T-lymphocytes kill virus-infected or tumor cells

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