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Effector T-cells, effector T-cell functions. Activation of effector T-cells is less dependent on co-receptor signaling. Naive or „resting” T cells… relentless migration and recirculation, LN, lymph, blood… For several month, which is its lifespan.
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Activation of effector T-cells is less dependent on co-receptor signaling Naive or „resting” T cells… relentless migration and recirculation, LN, lymph, blood… For several month, which is its lifespan
T-cell activation changes the expression of multiple receptors Integrin VLA-4 enables effector T-cells to home in inflamed tissues
EFFECTOR T LYMPHOCYTES Effector T cells interact with and act on antigen presenting cells Effector T cells secrete cytokines and cytotoxins
Environmental factors and interactions with APCs initiate distinct differentiation programs in naive T-cells
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
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
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
Responses to Mycobacterium leprae are sharply differentiated in tuberculoid and lepromatous leprosy.
POLARIZATION OF HELPER T LYMPHOCYTES IS DIRECTED BY DENDRITIC CELL DERIVED AND AUTOCRINE CYTOKINES AND TRANSCRIPTION FACTORS
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
Granulomas develop when intracellular pathogens resist elimination
Th2 cellsstimulatetheproliferation and differentiation of naive B cells
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
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
Human Ig classes and subclasses Complement activation Classical Alternative FcR binding IgM ++++ ++ - IgG1 ++++ ++ +++ IgG2 + ++ + IgG3 +++ ++ ++++ IgG4 +/- ++ + IgA - +++ +++ IgE - ++ +++ IgD - ++ -
ACTIVATION CD4+ Th CD40L IL-2 B7 CD28 CD8+ Tc PRIMING OF CD8+ CYTOTOXIC T CELLS • 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
KILLING OF INFECTED CELLS BY CTL Recognition by CTLs induces secretion of cytotoxins to the target cell
PHYSIOLOGICAL AND PATHOLOGIC CELL DEATH Apoptotic signal Cell demage
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)
MECHANISM OF CELLULAR KILLING BY CD8+ CYTOTOXIC T LYMPHOCYTES Proteoglycans H2O, Ca++, ions Polymerized perforin Granzyme APOPTÓZIS CYTOKINE RELEASE CD8+ T CELL TARGET CELL
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
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
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 SEGÍTŐ T SEJTEK Naive CD4+ T cell CD4 TCR KÖLCSÖNHATÁS AKTIVÁCIÓ INSTRUKCIÓ
EFFEKTOR T LIMFOCITÁK JELLELMZŐ MOLEKULÁI 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+