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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