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

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

Cytotoxic T cells Th1 cells Th2 T cells

Virus infected cellMacrophage

containing bacteriaB cell presenting specific antigen

CytotoxinsPerforin

Granzyme

CytokinesFasLIFNγ

TNF-βTNF-α

ActivationIFNγ

GM-CSFTNF-αCD40LFasL

CytokinesIL-3

GM-CSFIL-10TGFβ

Eotaxin

ActivationIL-4IL-5

CD40L

CytokinesIL-3

TNF-βIL-2

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

DCΦ

NK cell

IL-12

CD8+ cytotoxic T cell

IL-12

IL-12 FAVORS POLARIZATION TO TH1-TYPE

EFFECTOR T-CELLS

Th0Th1

IL-12IFNγ

IFNγ

Th2

IL-2IFNγTNF-βGM-CSFIL-3

IL-4IL-5IL-10IL-13

IL-10 FAVORS POLARIZATION TO Th2

Th0IL-10

Th1

IL-2IFNγTNF-βTNF-αGM-CSFIL-3

DC

Self tissue, tumor cell

IL-10

Makrofág

Th2

IL-4IL-5IL-10IL-13

TOLERANCE

EFFECTOR CD4+ HELPER T LYMPHOCYTES SECRETE DIFFERENT CYTOKINES

Inflammatory cytokines

CELLULAR IMMUNE RESPONSE

Anti-inflammatory cytokines

HUMORAL IMMUNE RESPONSE

IFNIFNγγ, IL-2, TNF-, IL-2, TNF-ββ/LT/LT

Th1 Th0

IL-4, IL-5, IL-6, IL-10IL-4, IL-5, IL-6, IL-10

Th2IL-4IFNγ

Responses to Mycobacterium leprae are sharply differentiated in tuberculoid and

lepromatous leprosy.

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

TRANSCRIPTION FACTORSTRANSCRIPTION FACTORS

Th1 DCΦ

IFNγ

Th2 B

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

CD40

CD40L

CD40L

EFFECTOR FUNCTIONS OF TH1 CELLS

Granulomas develop when intracellular pathogens resist elimination

TH2 functions

Th2 cells stimulate the proliferation and differentiation of Th2 cells stimulate the proliferation and differentiation of naive B cellsnaive 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-2IL-4IL-5

B cell proliferation and differentiation – isotype switch

IL-2IL-4IL-5 IgM

IgG

IgA

IgE

IL-2IL-4IL-6IFNγ

IL-5TGFβ

IL-4

REGULATION OF ISOTYPE SWITCH OF B CELLS

Human Ig classes and subclasses

IgM ++++ ++ -

IgG1 ++++ ++ +++

IgG2 + ++ +

IgG3 +++ ++ ++++

IgG4 +/- ++ +

IgA - +++ +++

IgE - ++ +++

IgD - ++ -

Complement activation

Classical Alternative FcR binding

Cytotoxic T-cells

PRIMING OF CD8+ CYTOTOXIC T CELLS

CD28

CD8+Tc

B7

APC

CD40

M HC I

CD4+ThCD40L

ACTIVATION

IL-2

PRIMING OF CD8+ 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

Apoptosis

Macrophage Granulocyte, macrophage

Inflammatorycytokines

IL-1TNFIL-6

a

Necrosis

DNS-ladder

PHYSIOLOGICAL AND PATHOLOGIC CELL DEATH

Apoptotic signal Cell demage

Healthy cell Necrotic 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)

MHC+peptide

TCR

CD8

FasL

Fas

Crosslinking

ICE/CASPASE

MECHANISM OF CELLULAR KILLING BY CD8+ CYTOTOXIC T LYMPHOCYTES

CD8+ T CELL TARGET CELL

H2O, Ca++, ions

Granzyme

Polymerized perforin

APOPTÓZIS

Proteoglycans

CYTOKINE RELEASE

Soluble TNF

TNF-α

TNF-β/LTα

LTβLTαLTβ

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

CTLeffector Target cell

Killedtarget cell

perforingranzyme B

Antigen recognizing receptorDeath domain

TNFRItrimerization

TNFRItrimerization

TNFRItrimerization

Fastrimerization

Fastrimerization

Fastrimerization

sFasL

sTNF

TNF

TNF

FasL

FasL

T sejt T sejt

MECHANISMS OF FAS RECEPTOR – MEDIATED PROGRAMED CELL DEATH

Cytotoxic T lymphocytes recognizevirus-infected or tumor cells

Activated cytotoxic T-lymphocyteskill virus-infected or tumor cells

CONSEQUENCE OF T CELL-MEDIATED IMMUNE RESPONSES

TCR

CD4

Naive CD4+ T cellNaive CD4+ T cell

Th0 blasztTh0 blaszt

TCR

CD4

CD4

TCR

Th1Th1 Intracelluláris patogén GyulladásTc aktivációIgG1 & IgG3 ellenanyagADCC, opszonizációKomplement aktiváció

TCR

CD4 Th2Th2Extracelluláris patogénSoksejtek parazitaSzekretoros IgA IgE, allergia

TCR

CD4 TregTregTh1 gátlásTolerancia fenntartása

KLONÁLIS OSZTÓDÁSKLONÁLIS OSZTÓDÁSDIFFERENCIÁCIÓDIFFERENCIÁCIÓ

EPIGENETIKAIEPIGENETIKAI VÁLTOZÁS, MEMÓRIAVÁLTOZÁS, MEMÓRIA

KÖLCSÖNHATÁSKÖLCSÖNHATÁSAKTIVÁCIÓAKTIVÁCIÓ

INSTRUKCIÓINSTRUKCIÓ

Th17Th17Extracelluláris patogénGyulladásAutoimmun betegségekAllergia

TCR

CD4

EFFEKTOR SEGÍTŐ T SEJTEKEFFEKTOR SEGÍTŐ T SEJTEK

DCDC

TCRTCR++

CD4CD4++

CD28CD28++

CD25CD25++

Th1Th1

T-bet

CCR1CCR5CXCR3

CD45RBlo

IL-12Rα

LAG3

Th2Th2

GATA3

CCR4CCR3CXCR4

CD45RBhigh

IL-1R

CD30

Th17Th17

RORγt

IL-23R

CCR6

CD127IL-7Rα↓

CTLA4B7 ligand

GITR

CD25IL-2Rα

TregTreg

FoxP3

EFFEKTOR T LIMFOCITÁK JELLELMZŐ MOLEKULÁI