ANTIGEN-SPECIFIC T – CELL ACTIVATION

PARTNERS

Antigen presenting cell carrying antigenic peptides bound to MHC – pre-formed MHC – peptide

complexes

Self MHC with captured antigenic peptide interacts with antigen-specific T lymphocytes selected from

the available T cell repertoire

INTERACTION

MHC – peptide complex (ligand)

T cell receptor

Normal cell Infected cell

T

RECOGNITION OF CORRECT MHC – PEPTIDE COMPLEXES BY THE SPECIFIC T-CELL

APC AND T CELL INTERACTION

IS IT SUFFICIENT FOR T CELL ACTIVATION?

WHERE AND WHEN CAN OCCUR?

HOW IS IT INDUCED?

0 10

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0 10

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110 120

CDR1 CDR2 CDR3

-chain

-chain

CDR1 CDR2 CDR3

V C

-CHAIN

Diszulfid hidak

CDR1 and CDR2 are not hypervariable

NO SOMATIC HYPERMUTATION

Variability of CDR3 is the result of joining variability

NH2

COOH

VARIABILITY AND ORIENTATION OF CDR IN THE T CELL RECEPTOR

N

N

C

CMHC

MHC

N

N

C

CMHC

MHC

N

N

C

CMHC

MHC

1

2

3 1

2

3

INTERACTION OF THE T - CELL ANTIGEN RECEPTOR WITH AN MHC – PEPTIDE COMPLEX

1. The TCR is monovalent, binds a single MHC – peptide complex

2. The affinity of the TCR – peptide – MHC interaction is low 10-5 - 10-6 M/l

3. A defined MHC – antigenic peptide complex is displayed in the cell membrane together with various other MHC – peptide complexes (DILUTED LIGAND)

4. How many MHC – peptide complexes are needed for T cell signaling?

TCR - MHC1

TCR - MHC1

CDR3 - peptide

APC T

THE IMMUNOLOGICAL SYNAPSE

THE IMMUNOLOGICAL SYNAPSE

T CELL

ANTIGEN PRESENTING CELL

CD48

CD2

ICAM-1

LFA-1

B7

CD28CD4

SIGNALING COMPLEX

adaptor

ACTIVATEDT CELL

ICAM – Intercellular Adhesion Molecule

APC

T cell

interaction recognition

1 2 3 4

5 6 7 8

stabilization separation

Negulescu P.A. et. al. Immunity 4: 421-430, 1996

THE INTERACTION OF T CELLS AND ANTIGEN PRESENTING CELLS

?

C D 4 5 R O

C D 5

C D 4

C D 3

C D 2

C D 2 8

C D 1 5 2 ( C T L A - 4 )

C D 4 9 d / 2 9 ( V L A - 4 )

C D 1 5 4 ( C D 4 0 L )

C D 4 0

C D 2 2

C D 7 2

M H C I I

C D 5 8 ( L F A - 3 )

C D 5 9

C D 8 0 ( B 7 - 1 )

C D 8 6 ( B 7 - 2 )

C D 2 0

C D 4 3

C D 1 0 6 ( V C A M )

C D 5 4 ( I C A M - 1 )C D 1 1 a / 1 8 ( L F A - 1 )

C D 1 0 2 ( I C A M - 2 )

C D 5 0 ( I C A M - 3 )

C D 1 9

C d 7 9bC d 7 9a

s I g M

C D 2 1 ( C R 2 )

C D 8 1 ( T A P A )

C D 2 3 ( F c R I I )e

M H C I

C D 8

BCR

TCR

THE CONTACT OF APC AND T CELLS IS STABILIZED BY ADHESION MOLECULES

*

*

*

*

**

B CELL T CELL

MHCI – CD8

MHCII – CD4

CD40 – CD40L

B7 – CD28

KINETICS OF LYMPHOCYTE ACTIVATION

ANTIGEN SIGNAL1.

Ko-receptorAdhesion molecule

Cytokines SIGNAL2.

Resting lymphocyte G0PTK activation RNA synthesis Free Ca++ Protein synthesis Protein phosphorylation DNA synthesis

Lymphoblast

0 10sec 1min 5min 1hr 6 hrs 12 hrs 24 hrs

Nyugvó limfocita G0

G1

G2

M

Ssejtosztódás

DNA synthesis

Effector cell Memory cell

Transport Membrane changeRNA and protein synthesis

Resting lymphocyte G0

Similar but not identical signaling elements in B and T Similar but not identical signaling elements in B and T cellscells

BCRBCR TCRTCR

Ly

n

KinasesKinasesSykSyk

BtkBtk

fyn

ZAP70ZAP70ItkItk

SLP-65/BLNKSLP-65/BLNK

PLCPLC22

Adaptors +Adaptors +substratessubstrates

PLCPLC11

SLP-76SLP-76

Antigen

BCR

Antigen

MHC

TCR

CD3

APC

s s

ss

ss

s

ss

V V

C C

s

α βss

ss

ss

ss

CD3

s s

ε δ ε γζ ζ

D/E X7 D/E X2 X7 YXXL/I YXXL/IP P

ITAMImmunoreceptor Tyrosine-based

Activation Motif

ACTIVATION

T CELL RECEPTOR MEDIATED SIGNALING

Multisubunit Immune Recognition Receptors

MIRR

transzkrip ciós fak to rok fosz forilá ció ja kora i génexpre ssz ió

M HC+antigén

CD4

CD28

A PC

T-sejtreceptor

CskCa +2

IP3

-P Lck

RafPtdIns3,4,5P3

PtdIns4,5P2

M APK

ZA P-70

Fyn

NFAT

NFAT

AP -1O CT

NF- B

NF- B

DAGLAT

PLC Sos SosRas

CD45

PKCPKC

LATCbl Grb2

VavRho/Rac

SLP76

I B

NF- B

I BP P

NFATP P

CNCN

PI3K

Ca +2Ca2+

Ca2+Ca2+

Ca2+

Ca2+

Ca +2

INTRACELLULAR EVENTS OF T CELL ACTIVATION

NEW GENES

SIGNAL TRANSDUCTION

Enzimatic modification(kinases, phosphatases,

proteases)

Local concentration(recruitment orsequestration of

interacting components

Timing(pathway can go to diverse

directions,first one will be realized)

Allosteric effects(binding activates or

inactivates)

CONVERGING SIGNALING PATHWAYS IN T CELL ACTIVATION

CD4/CD8 costimulationCD28 costimulation

INTERACTION OF THE TCR WITH MHC-PEPTIDE COMPLEXES IS ESSENTIAL BUT NOT SUFFICIENT

FOR T-CELL PRIMING

INVOLVEMENT OF ADHESION AND CO-STIMULATORY MOLECULES

Lck

ss

ss

ss

ssV4

V1

V2

V3

Helper T-cell

CD4

CD4 T-sejt+

MHCII+

peptid

TCR CD4

APC

p56lck

CD8TCR

MHCI+

peptid

APC

CD8 T-sejt+

p56lck

THE ADHESION AND CO-STIMULATORY MOLECULES CD4 AND CD8

SIGNAL

2

1

2

1

PROFESSIONAL APC

CD8

b

ss

a

ss

LckCytotoxic T-cell

α β

TARGET CELL

1

3

2

2m

1

3

2

2m

MARKERS OF T CELL SUBPOPULATIONS

ADHESION MOLECULE

BINDS TO MHC

SIGNALING MOLECULE

THE RATIO OF CD4+/CD8+ T CELLS IS STABLE IN HEALTHY INDIVIDUALS

CD4+ : CD8+ = 1.6

Normal CD4+ T-cell counts = 600 – 1400/ l

HIV infection AIDS = CD4+ T cell count <200/l