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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
Az αβ and γδ T-cells recognize different antigens
Less V-segments, but the
Delta-chain has large
junctional diversity
Vg9Vd2 T cells can recognize
PAgs (such as isopentenyl
pyrophosphate, IPP) that are
accumulated in tumour cells
Pags: natural phospho-antigens
1-5 % of T-cells in the blood
But γδ T-cells are the dominant type in epithelia
Unlike 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 funkciók
Stressz-related proteinek
felismerése
British Journal of Haematology, 2013, 160, 123–132 doi:10.1111
Generation of T-cell receptor diversity
mehanizmusa
(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 TCR-rearrangement—similar to BCR
A β-chain rearrangement (like Ig heavy chain)
Efficiency of beta chain
rearrangement is about
80%
RAG-1 RAG-2 genes
become are inactivated
Timocyte proliferation
CD4, CD8 expressionó
TCR-rearrangement is similar to that of the BCR
The α-Chain rearrangement (Ig light chain)
B- AND T-CELL RECEPTORS SHARE BASIC
STRUCTURE
mIg H
mIg L

TCR
T cell receptor
TCR
V
TCR
C
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
T-CELL
Single binding
C site
No 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%) most
T-cells die of neglect.
( no survival signals)
α-chain rearrangement can
continue until the assembly of
a functional αβ receptor
has been assembled.
Selection of developing T-cells in the thymus
Bare lymphocyte syndrome
MHCI vagy MHCII deficiency
Lack of CD8+ or CD4+ cells
Role of co-receptors in the
development 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
Characteristics of antigen recognition by T-cells (TCR)
1. T-cells need antigen processing by APCs
2. T-cells recognize virus-infected cells
APC
ANTIGEN BINDING
NO
INTERACTION
T CELL
AKTIVATION
Antigén receptor
B-CELL
T-CELL
(review)
Phases of T cell response
A T-CELL SIGNALING IS INITIATED BY
PHOSPHORYLATION OF ITAMs
APC
MHC
Antigen
Antigen
TCR
BCR
αβ
s
V s
s
sV
s
C s
s
sC
ss
P
P
D/E X7 D/E X2 YXXL/I X7 YXXL/I
ITAM
Immunoreceptor Tyrosine-based
Activation Motif
ACTIVATION
CD3
CD3
εδ
s s
s s
εγ
s s
s s
ζζ
s s
Clustering of the T-cell receptor and a co-receptor
initiates signaling within the T cell.
(review)
TCR signaling
THE IMMUNOLOGICAL SYNAPSE
APC
T
APC
T SEJT
T SEJT – ANTIGÉN PREZENTÁLÓ SEJT
KÖLCSÖNHATÁS
interaction
Recognition/activation
1
2
3
4
5
6
stabilization
7
8
detachment
Ca-influx detectable in minutes by the changing colour of a Ca-sensitive dye
Negulescu P.A. et. al. Immunity 4: 421-430, 1996
AZ IMMUNOLOGICAL SYNAPSEÓGIAI
SZINAPSZIS
ANTIGEN PRESENTING CELL
ICAM-1
B7
CD48
CD4
CD2
CD28
adaptor
LFA-1
SIGNALING COMPLEX
T SCELL
ACTIVATED
T CELL
THE IMMUNOLOGICAL SYNAPSE
APC
T cell
CELL ADHESION AND SIGNALING IS FACILITATED BY MANY RECEPTORLIGAND INTERACTIONS
C D2 3 (Fc eRII)
CD8 1 (TAPA)
C D2 1 (CR2 )
CD 19
C d 7 9b
C d 7 9a
sIgM
MHCI – CD8
MHCII – CD4
CD40 – CD40L
BCR
B7 – CD28
C D43
C D11 a /1 8 (LFA- 1)
C D5 4 (IC AM-1 )
CD 10 2 (IC AM-2 )
C D5 0 (IC AM-3 )
CD 40
APC
CD 22
CD 72
C D45 RO
?
*
T CELL
C D5
CD4
M HC II
M HCI
*
C D15 4 (C D4 0 L)
TCR
*
C D3
C D58 ( LFA-3 )
CD 59
CD8
C D 8 0 (B7 - 1 )
C D 8 6 (B7 - 2 )
C D2
CD 20
C D 28
*
*
C D 1 5 2 ( C TLA- 4 )
C D1 06 ( VC AM)
C D49 d /2 9 (VLA-4 )
*
T-cell activation requires two signals
Signal 1 antigén & antigén
receptor
Th
APC
AKTIVÁCIÓ
Signal 2
B7 FAMILY (CD80 & CD86)
CD28
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
Second signals triggered by co-receptors are required for
T-cell activation
Th
Th
Th
CD40L
CD28
CD40
B7
B7
ACTIVATION