antigen presentation in a nutshell. antigen-specific t – cell activation partners antigen...

Antigen presentation in a nutshell

ANTIGEN-SPECIFIC T – CELL ACTIVATION

PARTNERS

Antigen presenting cell carrying antigenic peptides bound to MHC – pre-formed MHC – peptide complexes – INDEPENDENT OF T CELLS

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

T-sejt

TCR

APC

MHC

T-sejt T-sejt

TCR TCR

APC

MHC

APC

MHC

MHC RESTRICTION

One single T-cell receptor can recognize a given MHC – peptid complex

The TCR-specific peptide is recognized only when its presented with an MHC on which the TCR had been selected during its development in the thymus

If the peptide binds to another MHC molecule no T-cell recognition occurs

If the same MHC molecule binds another peptide, no T-cell recognition occurs

MMOUSEOUSE YY

Virus AVirus A T -T - CELLS CELLS

TT

TTTT

TTTT TT

Virus BVirus B+ + YY cellscells

TT

Virus AVirus A+ + YY cellscells

TT

MMOUSEOUSE X X

Virus AVirus A+ + X X cellscells

TT

Virus AVirus A+ + X X cellscells

TT

TT

THE EXPERIMENT OF DOHERTY & ZINKERNAGEL 1976

The virus infected cell must derive from the same strain as the T cell

They have to be MHC identical

Specific for self and virus

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

10

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0 10

10

20

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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) most complexes are MHC/peptide complexes

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

TCR - MHC1

TCR - MHC1

CDR3 - peptide

APC T

THE IMMUNOLOGICAL SYNAPSE

25.6_immuno_synapse.mov

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

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

7-1_TCR_Signaling.mov

TCR signalling

Fyn

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

Role of transcription factors in T-sejt activation

TCR signaling

?

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.

co-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

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