T-cell development and differentiation

T-cell diversity is generated in the thymus

The TCR is a recognition unit that looks like an arm of the BCR

In which the μ and β chains, and the light chains and the α-chains are homologuos

The main mechanisms of gene rearrangements are similar for the TCR and BCR

CDR1,2, 3, loops in theTCRα and TCRβ chains

A T-cell precursors migrate from the bone marrow to thymus

T-cell markers are induced after thymocytes interact with the thymic epithelial cells

A Notch-1receptor and its cytoplasmic region, acting as a transcription factor is required for the development

of the T-cell lineage

Less V-segments, but theDelta-chain has large junctional diversity

Vg9Vd2 T cells can recognizePAgs (such as isopentenyl pyrophosphate, IPP) that areaccumulated in tumour cellsPags: natural phospho-antigens

Az αβ and γδ T-cells recognize different antigens

1-5 % of T-cells in the blood But γδ T-cells are the dominant type in epitheliaUnlike αβ T-cells recognition of antigens by γδ T-cells is independent of MHC. They recognize phosphorylated metabolites produced by many microbes. Tumor-specific immune response

Multiple functions of gamma-delta T cells.

NK funkciókStressz-related proteinek felismerése

British Journal of Haematology, 2013, 160, 123–132 doi:10.1111

Generation of T-cell receptor diversitymehanizmusa

(occurs in the thymus)

Si milar to that of B cells’… BUT!!1.No diversification after activation

2. No secreted form

Diversity of the BCR and the TCR

The αβ and γδ T-cell lineages develop from a common precursor

A β-chain rearrangement (like Ig heavy chain)

A TCR-rearrangement—similar to BCR

Efficiency of beta chain rearrangement is about 80%

RAG-1 RAG-2 genes become are inactivated

Timocyte proliferation CD4, CD8 expressionó

The α-Chain rearrangement (Ig light chain)

TCR-rearrangement is similar to that of the BCR

C

mIg H

mIg L

TCR

TCR

TT-CELL-CELL

C

VT cell receptor T cell receptor TCRTCR

B- AND T-CELL RECEPTORS SHARE BASIC STRUCTURE

TCR = +

The variable region of the -chain is generated by gene rearrangements of the V – D – J gene segments

analogous to the generation of IgH diversity

The variable region of the -chain is generated by the recombination of V and J analogous to IgL

Single binding siteNo somatic

mutation

Main steps of T-cell development, gene rearrangemnts, changes in gene expression

Shaping the T-cell repertoire.Positive and negative selection Thymus

Few TCR reacts with the MHC (about 2%) mostT-cells die of neglect. ( no survival signals)

α-chain rearrangement can continue until the assembly ofa functional αβ receptor has been assembled.

Selection of developing T-cells in the thymus

Bare lymphocyte syndrome

MHCI vagy MHCII deficiencyLack of CD8+ or CD4+ cells

Role of co-receptors in thedevelopment of single + T-cells

DC Macrophage in medulla of Thymus. Special transcription factor expressed… AIRE.Tissue spec. Antigens expressed

AIRE mutaton: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy

Multiple stages of T-cell development in the thymus

CD25+ FoxP3+ cells

FoxP3-deficiency: autoimmune disease

IPEX: immune dysregulation polyendocrinopathy, enteropathy, X-linked syndrome

T-cell activation

ANTIGEN BINDING

NO

INTERACTION

APC

T CELL AKTIVATION

AntigAntigén receptorén receptor

TT-CELL-CELL B-CELLB-CELL

Characteristics of antigen recognition by T-cells (TCR)

1. T-cells need antigen processing by APCs

2. T-cells recognize virus-infected cells

Phases of T cell response(review)

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

A T-CELL SIGNALING IS INITIATED BY PHOSPHORYLATION OF ITAMs

Antigen

BCR

Antigen

Clustering of the T-cell receptor and a co-receptor initiates signaling within the T cell.

TCR signaling(review)

APC T

THE IMMUNOLOGICAL SYNAPSE

T SEJT

APC

interaction Recognition/activation

1 2 3 4

5 6 7 8

stabilization detachment

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

T SEJT – ANTIGÉN PREZENTÁLÓ SEJT KÖLCSÖNHATÁS

Ca-influx detectable in minutes by the changing colour of a Ca-sensitive dye

AZ IMMUNOLOGICAL SYNAPSEÓGIAI SZINAPSZIS

T SCELL

ANTIGEN PRESENTING CELL

CD48

CD2

ICAM-1

LFA-1

B7

CD28CD4

SIGNALING COMPLEX

adaptor

ACTIVATEDT CELL

T cell

APC

THE IMMUNOLOGICAL SYNAPSE

?

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

CELL ADHESION AND SIGNALING IS FACILITATED BY MANY RECEPTOR-LIGAND INTERACTIONS

*

*

*

*

**

APC T CELL

MHCI – CD8

MHCII – CD4

CD40 – CD40L

B7 – CD28

T-cell activation requires two signals

APC Th

Signal 1 antigén & antigénreceptor

Signal 2

B7 FAMILY (CD80 & CD86) CD28

AKTIVÁCIÓ

The professional APCs (dendritic cells, macrophages, B-cells) express or upregulate co-receptors that deliver the 2nd signals.

Regular tissue-derived cells fail to express co-receptors

Th

Second signals triggered by co-receptors are required for T-cell activation

Th

CD40

CD40L

B7B7

CD28

Th

ACTIVATION