PLASMA CELL

ANTIGEN

CYTOKINES

B -CELL

T – CELLS PROMOTE B – CELL DIFFERENTIATION

ISOTYPE SWITCH AND AFFINITY MATURATION OCCURS IN COLLABORATION WITH T – CELLS ONLY

WHAT IS THE STRUCTURE OF THE T – CELL RECEPTOR?

C

mIg H

mIg L

TCR

TCR

TT-SEJT-SEJT

C

VAntigAntigen receptoren receptorTCRTCR

B and T cell receptors are similar

TCR = +

The -chain variable region is assembled from V – D – J gene segments by recombination – analogous with IgH

chainThe α-chain variable region is assembled from V – J gene segments by recombination – like in IgL - chain

Single binding siteNo somatic

mutation

Chr 7

Chr 14

5' 3'

5' 3'

5' 3'

5' 3'

-chain locus

and δ-chain locus

-chain locus

-gene rearrangement results in the elimination of the δ gene

Sequence of D genes allows reading in 3 reading frames

No strict 12 – 23 rule for δ-genes (DJ and VD recombination)

Chr 7

TCR1 =

TCR2 = δ

LOCATION OF TCR GENES

L1 V1 Ln Vn D1 J1 C1 D2 J2 C2

-enhancer

L1 V1 Ln Vn J1 C1 J2 C2

-silencer, enhancer

L1 Vδ1 L2 Vδ2 L3 Vδ3 Dδ1Dδ2Dδ3Jδ1Jδ2Jδ3 Cδ L4 Vδ4

L1 V1 Ln Vn J1-n C1

TT-CELL-CELLAntigAntigen receptoren receptor

TCRTCR

VV

CC

The VARIABLE REGIONS OF - AND -CHAINS ARE GENERATED BY SOMATIC RECOMBINATION

mRNS

not functional

Recombination of V and J genes can occur after multiple unsuccessful recombination

next funcional

further functional (no allele exclusion)

0 10

10

20

20

30

30

40

40

50

50

60

60

70

70

80

80

90

90

100

100

110 120

0 10

10

20

20

30

30

40

40

50

50

60

60

70

70

80

80

90

90

100

100

110 120

CDR1 CDR2 CDR3

-chain

-chain

CDR1 CDR2 CDR3

V C

-CHAIN

Diszulfid hidak

CDR1 and CDR2 loops are not hypervariable

NO SOMATIC HYPERMUTATION

Variability of CDR3 is the result of joining variability

NH2

COOH

GÉNEK/KAPCSOLÓDÁS

IMMUNOGLOBULIN

H /

VARIABLE (V) 65 70

DIVERZITY (D) 27 0

D (3 frame) rare -

JOINING (J) 6 5/4

JOINING + P + N 2 1

V GENE PAIRS 3.4x106

JOINING ~3x107

TOTAL ~1014

SOMATIC HYPERMUTATON

ESTIMATED VARIABILITY OF IMMUNOGLOBULIN AND T-CELL RECEPTOR GENES

T CELL RECEPTOR

52 ~70

2 0

OFTEN -

13 61

2 1

5.8x106

~2x1011

1018

NO

PLASMA CELL

ANTIGEN

CYTOKINES

B -CELL

T – CELLS PROMOTE B – CELL DIFFERENTIATION

ISOTYPE SWITCH AND AFFINITY MATURATION OCCURS IN COLLABORATION WITH T – CELLS ONLY

HOW T – CELLS RECOGNIZE ANTIGENS?

ANTIGEN BINDING

NO INTERACTION

ACCESSORY CELL

T-CELL ACTIVATION

AntigeAntigen receptorn receptor

TT-CELL-CELL B-CELLB-CELL

CHARACTERISTICS OF T-CELL ANTIGEN RECOGNITION

1. The TCR is not able to interact directly with soluble or cell-bound antigen

2. T-cell activation can be induced by antigen in the presence of acessory cells, only

3. T-cells recognize virus-infected cells

T-LYMPHOCYTES RECOGNIZE VIRUS-INFECTED CELLS

Virus-infected cellCytotoxic T-lymphocytes kill

virus-infected cells

virus

Killed virus-infected cellInfected cell

Citotoxic T-cell

T-cells do not interact with virus particles

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 organism as the T cell

Specific for self and virus

THE MAJOR HISTOCOMPATIBILITY GENE COMPLEX

MHC

MMouseouse XXThymus Thymus removalremoval

((No No TT cellscells))

MMouseouse YY

MMouseouse X X

ORGAN REJECTION IS MEDIATED BY T-CELLS

MMouseouse X X ((YY))MMouseouse YY

MMouseouse YY and the congenic and the congenic MMouse ouse XX((YY)) carry carry an identical an identical MHCMHC gene locus gene locus

TT-cells recognize -cells recognize pproducts of MHC genes as sroducts of MHC genes as seelf or non-selflf or non-self

CONGENIC MICE SHARE COMMON MHC GENES

If any cell of an individual starts to produce foreign (viral or bacterial) or abnormal If any cell of an individual starts to produce foreign (viral or bacterial) or abnormal (tumor associated) proteins, the T-cells recognize these antigen presenting cells (tumor associated) proteins, the T-cells recognize these antigen presenting cells

as altered self cells and respond against themas altered self cells and respond against them

HISTOCOMPATIBILITY IS DETERMINED BY GENES OF THE MHC

MMouseouse X XMMouseouse YY

TThe immune response to protein antighe immune response to protein antigeens is also dependent on MHC ns is also dependent on MHC genesgenes

Protein antigens are tProtein antigens are taaken up from the environment by phagocytic ken up from the environment by phagocytic cells and via MHC proteins present for T-lymphocytes cells and via MHC proteins present for T-lymphocytes

THE MAJOR HISTOCOMPATIBILITY GENE COMPLEX AND THE RESPONE TO PROTEIN ANTIGENS

Antigen

IMMUNE RESPONSE NO IMMUNE RESPONSE

Antigen

T-LYMPHOCYTES RECOGNIZE ANTIGEN-DERIVED PROTEIN FRAGMENTS (PEPTIDES) EXPRESSED ON THE SURFACE OF SELF

ANTIGEN PRESENTING CELLS

VIRUS-INFECTED CELLS ARE RECOGNIZED BY T-LYMPHOCYTES IN MHC-DEPENDENT MANNER

TISSUE TRANSPLANTATION IS RESTRICTED BY MHC MOLECULES

THE IMMUNE RESPONSE TO PROTEIN ANTIGENS IS REGULATED BY INDIVIDUALLY POLYMORPHIC MHC GENES

ANTIGEN PRESENTING CELLSANTIGEN PRESENTING CELLS

Synthesize antigens – endogenous antigensendogenous antigens (virus, tumor)

Internalize antigens – exogenous antigensexogenous antigens (any protein)

Degrade protein antigens to peptides – processingprocessing

Protein – derived peptides are presented by MHC (HLA) membrane proteins – antigen presentationantigen presentation

MHC molecules present both self and non-self protein MHC molecules present both self and non-self protein – derived peptides– derived peptides

MHC class I molecules are expressed in all nucleated MHC class I molecules are expressed in all nucleated cellscells

MHC class II molecules are expressed by professional MHC class II molecules are expressed by professional antigen presenting cellsantigen presenting cells

ANTIGEN RECOGNITION BY T-CELLS REQUIRESPEPTIDE ANTIGENS AND ANTIGEN PRESENTING CELLS

THAT EXPRESS MHC MOLECULES

YT

No T-cell response

soluble Ag

Native membrane Ag

Peptide antigen

Cell surface MHC-peptide complex

T-cell response

Cell surfacepeptides APC

PROFESSIONAL ANTIGEN PRESENTING CELLS

Express MHC class I and class II proteins in the cell membrane

Express co-stimulatory molecules (CD40, B7)

B cells – specialized for soluble proteins, toxins

ADAPTIVE

Macrophages – extracellular pathogens (bacteria, yeast)

Dendritic cells – viruses, apoptotic cells

INNATE

T-lymphocytes with αβ TCR recognize MHC – peptide complexes expressed on the surface of professional antigen presenting cells (APC) APC)

T-cell recognition requires the physical contact of APC and T cellT-cell recognition requires the physical contact of APC and T cell

TCR

APC

MHC

TCR TCR

APC

MHC

APC

MHC

MHC RESTRICTION OF T-CELL RECOGNITION

A given TCR recognizes a defined MHC – peptide complex

The same peptide presented by another MHC is not recognized by the same TCR

Another peptide bound to the same MHC is not recognized by the same TCR

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

AKTIVÁCIÓ

Assembly of TCR and BCR

Antigen

BCR

AntigenAntigen Antigen

F1F1

PPMMouseouse X XMMouseouse Y Y

F2F2

GENERATION OF MHC CONGENIC MICE

20 times20 times

MMouseouse X X ((YY))