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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 Naive or „resting” T cells… relentless migration and recirculation, LN, lymph, blood…for several month, which is its lifespan

  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 DCΦ 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 Makrofág 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-6, 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 DCΦ Th1 IFNγ

  14. 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+

  15. Th1 Intracelluláris patogén Gyulladás Tc aktiváció IgG1 & IgG3 ellenanyag ADCC, opszonizáció Komplement aktiváció CD4 TCR Th2 Extracelluláris patogén Soksejtek parazita Szekretoros IgA IgE, allergia CD4 DC TCR CD4 Th17 Extracelluláris patogén Gyulladás Autoimmun betegségek Allergia TCR CD4 TCR Th0 blaszt Treg Th1 gátlás Tolerancia fenntartása CD4 TCR KLONÁLIS OSZTÓDÁS DIFFERENCIÁCIÓ EPIGENETIKAI VÁLTOZÁS, MEMÓRIA EFFEKTOR HELPER T-CELLS Naive CD4+ T cell CD4 TCR KÖLCSÖNHATÁS AKTIVÁCIÓ INSTRUKCIÓ

  16. TH2 functions

  17. Th2 cellsstimulatetheproliferation and differentiation of naive B cells

  18. 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

  19. 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

  20. Human Ig classes and subclasses Complement activation Classical Alternative FcR binding IgM ++++ ++ - IgG1 ++++ ++ +++ IgG2 + ++ + IgG3 +++ ++ ++++ IgG4 +/- ++ + IgA - +++ +++ IgE - ++ +++ IgD - ++ -

  21. Cytotoxic T-cells

  22. PRIMING OF CD8+ CYTOTOXIC T CELLS

  23. 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

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

  25. PHYSIOLOGICAL AND PATHOLOGIC CELL DEATH Apoptotic signal Cell demage

  26. Healthy cell Necrotic cell Late apoptotic cell Apoptotic cell APOPTOSIS AND NECROSIS • HIGHLY REGULATED PROCESS • Induction • Excecution • Mitochondrial function  * Activation of caspases • Electron transzport  * Serine protease,calpain, proteasome • Oxidative phosphorylateion  * Redox potential • ATP synthesis  *DNA degradation (endonuclease)

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

  28. 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

  29. MECHANISMS OF FAS RECEPTOR – MEDIATED PROGRAMED CELL DEATH

  30. 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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