a a Activated T-cell Mature naive T-cell Memory T-cell T-CELL DIFFERENTIATION IN THE PERIPHERY Ag CD4 TCR APC CD8 TCR APC CD4 TCR APC CD8 TCR APC CD4 TCR APC CD8 TCR APC Ag Naive or „resting” T cells… relentless migration and recirculation, LN, lymph, blood…for several month, which is its lifespan

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 PERIPHERAL TOLERANCE IMMUNE RESPONSES ARE NOT INITIATED IN THE PERIPHERY

Environmental factors and interactions with APCs initiate distinct differentiation programs in naive T-cells T-CELL DIFFERENTIATION

Arming of effector T cells APC T Activation of NAÏVE T cells by signal 1 and 2 is not sufficient to trigger effector function, but….. IL-2 Effector T cell Clonal selection and differentiation How can this cell give help to or kill cells that express low levels of B7 family costimulators? 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

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

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

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

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

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

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

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

EFFECTOR CD4+ HELPER T LYMPHOCYTES SECRETE DIFFERENT CYTOKINES Inflammatory cytokines CELLULAR IMMUNE RESPONSE Anti-inflammatory cytokines HUMORAL IMMUNE RESPONSE IFNγ, IL-2, TNF-β/LT Th1 Th0 IL-4, IL-5, IL-6, IL-10 Th2 IL-4IFNγ

Th1 DC Φ IFNγ Th2B IL - 4 B7 expression  antigen presentation Germinal center formation Affinity maturation Isotype switch Memory B cell generation B7 expression  antigen presentation MHC-II expression  antigen presentation Mature dendritic cell Activated macrophage SUBSETS OF HELPER T LYMPHOCYTES COLLABORATE WITH DIFFERENT PROFESSIONAL ANTIGEN PRESENTING CELLS CD40 CD40L

TCR + CD4 + CD28 + CD25 + Th1 T-bet CCR1 CCR5 CXCR3 CD45RB lo IL-12Rα LAG3 Th2 GATA3 CCR4 CCR3 CXCR4 CD45RB high IL-1R CD30 Th17 RORγt IL-23R CCR6 CD127 IL-7Rα ↓ CTLA4 B7 ligand GITR CD25 IL-2RαTreg FoxP3 CHARACTERISTICS OF EFFECTOR HELPER T LYMPHOCYTES

TCR CD4 Naive CD4+ T cell Th0 blaszt TCR CD4 TCRTh1 Intracelluláris patogén Gyulladás Tc aktiváció IgG1 & IgG3 ellenanyag ADCC, opszonizáció Komplement aktiváció TCR CD4 Th2 Extracelluláris patogén Soksejtek parazita Szekretoros IgA IgE, allergia TCR CD4 Treg Th1 gátlás Tolerancia fenntartása KLONÁLIS OSZTÓDÁS DIFFERENCIÁCIÓEPIGENETIKAI VÁLTOZÁS, MEMÓRIA VÁLTOZÁS, MEMÓRIA KÖLCSÖNHATÁSAKTIVÁCIÓINSTRUKCIÓ Th17 Extracelluláris patogén Gyulladás Autoimmun betegségek Allergia TCR CD4 EFFEKTOR HELPER T-CELLS DC

TH2 functions

Th2 cells stimulate the proliferation 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

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

Human Ig classes and subclasses IgM IgG IgG2++++ IgG IgG4 +/-+++ IgA IgE IgD-++- Complement activation ClassicalAlternative FcR binding

Cytotoxic T-cells

PRIMING OF CD8+ CYTOTOXIC T CELLS

CD28 CD8+ Tc B7 CD4+ Th CD40L ACTIVATION IL-2 PRIMING OF CD8+ CYTOTOXIC T CELLS THROUGH COLLABORATION OF HELPER AND CYTOTOXIC T-CELLS 1.Dendritic cells with high B7 expression activate CD8+ T cells directly 2.Dendritic cells activate CD4+ T cells, which in turn enhance the co- stimulatory activity of dendritic cells 3.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 cellNecrotic cell Apoptotic cell Late apoptotic cell APOPTOSIS AND NECROSIS HIGHLY REGULATED PROCESS 1.Induction 2.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 CD8+ T CELLTARGET CELL H 2 O, Ca++, ions Granzyme Polymerized perforin APOPTÓZIS Proteoglycans CYTOKINE RELEASE

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

MECHANISMS OF FAS RECEPTOR – MEDIATED PROGRAMED CELL DEATH

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