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T – CELLS PROMOTE B – CELL DIFFERENTIATION
ANTIGEN
CYTOKINES
B -CELL
PLASMA CELL
ISOTYPE SWITCH AND AFFINITY MATURATION OCCURS IN
COLLABORATION WITH T – CELLS ONLY
WHAT IS THE STRUCTURE OF THE T – CELL RECEPTOR?
B and T cell receptors are similar
mIg H
mIg L

TCR
Antigen receptor
TCR
V
TCR
C
TCR =  + 
The -chain variable region is assembled from V – D – J
gene segments by recombination – analogous with IgH
chain
The α-chain variable region is assembled from V – J
gene segments by recombination – like in IgL - chain
T-SEJT
Single binding
C site
No somatic
mutation
-chain locus
L1 V1
5'
LOCATION OF TCR GENES
Chr 7
Ln Vn D1
J1
C1 D2 J2
C2
3'
-enhancer
 and δ-chain locus
TCR1 = 
Chr 14
5'
3'
-silencer, enhancer
L1 Vδ1 L2 Vδ2 L3 Vδ3
Dδ1Dδ2Dδ3Jδ1Jδ2Jδ3
Cδ L4 Vδ4
5'
3'
-gene rearrangement results in the elimination of the δ gene
-chain locus
L1 V1
5'
Ln Vn
Chr 7
J1
C1
J2
C2
3'
Sequence of D genes allows reading in 3 reading frames
No strict 12 – 23 rule for δ-genes (DJ and VD recombination)
TCR2 = δ
The VARIABLE REGIONS OF - AND -CHAINS ARE
GENERATED BY SOMATIC RECOMBINATION
Recombination of V and J genes can occur
after multiple unsuccessful recombination
not functional
T-CELL
Antigen receptor
TCR
/
next funcional
V
C
further functional (no allele exclusion)
mRNS
100
-chain
90
80
70
60
-CHAIN
50
40
30
20
NH2
10
0
10
20
30
CDR1
40
50
60
70
80
CDR2
Diszulfid hidak
90 100 110 120
CDR3
COOH
100
90
-chain
80
70
60
V
50
40
CDR1 and CDR2 loops are not
hypervariable
30
20
10
0
C
NO SOMATIC HYPERMUTATION
10
20
30
CDR1
40
50
60
CDR2
70
80
90 100 110 120
CDR3
Variability of CDR3 is the result of joining
variability
ESTIMATED VARIABILITY OF IMMUNOGLOBULIN AND T-CELL RECEPTOR
GENES
GÉNEK/
KAPCSOLÓDÁS
IMMUNOGLOBULIN
T CELL RECEPTOR
H
/


VARIABLE (V)
65
70
52
~70
DIVERZITY (D)
27
0
2
0
rare
-
OFTEN
-
JOINING (J)
6
5/4
13
61
JOINING + P + N
2
1
2
1
D (3 frame)
V GENE PAIRS
3.4x106
5.8x106
JOINING
~3x107
~2x1011
TOTAL
~1014
SOMATIC HYPERMUTATON
1018
NO
T – CELLS PROMOTE B – CELL DIFFERENTIATION
ANTIGEN
CYTOKINES
B -CELL
PLASMA CELL
ISOTYPE SWITCH AND AFFINITY MATURATION OCCURS IN
COLLABORATION WITH T – CELLS ONLY
HOW T – CELLS RECOGNIZE ANTIGENS?
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
ACCESSORY CELL
ANTIGEN BINDING
NO INTERACTION
T-CELL
ACTIVATION
Antigen receptor
B-CELL
T-CELL
T-LYMPHOCYTES RECOGNIZE VIRUS-INFECTED CELLS
T-cells do not interact with virus particles
VIrus-infected cell
Cytotoxic T-lymphocytes kill
virus-infected cells
Citotoxic T-cell
virus
Infected cell
Killed virus-infected cell
THE EXPERIMENT OF DOHERTY & ZINKERNAGEL 1976
T - CELLS
Virus A
Specific for self and virus
T
T
T T
T T
MOUSE Y
Virus B
+ Y cells
T
Virus A
+ Y cells
T
T
MOUSE X
Virus A
+ X cells
Virus A
+ X cells
T
T
The virus infected cell must derive from the same organism as the T cell
THE MAJOR HISTOCOMPATIBILITY GENE COMPLEX
MHC
Mouse Y
Thymus
removal
Mouse X
Mouse X
(No T cells)
HISTOCOMPATIBILITY IS DETERMINED BY
GENES OF THE MHC
ORGAN REJECTION IS MEDIATED BY T-CELLS
CONGENIC MICE SHARE COMMON MHC GENES
Mouse Y
Mouse X (Y)
Mouse Y and the congenic Mouse X(Y) carry
an identical MHC gene locus
T-cells recognize products of MHC genes as self or non-self
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
as altered self cells and respond against them
THE MAJOR HISTOCOMPATIBILITY GENE COMPLEX
AND THE RESPONE TO PROTEIN ANTIGENS
Antigen
Antigen
Mouse Y
IMMUNE RESPONSE
Mouse X
NO IMMUNE RESPONSE
The immune response to protein antigens is also dependent on MHC
genes
Protein antigens are taken up from the environment by phagocytic
cells and via MHC proteins present for T-lymphocytes
ANTIGEN PRESENTING CELLS
Synthesize antigens – endogenous antigens (virus, tumor)
Internalize antigens – exogenous antigens (any protein)
Degrade protein antigens to peptides – processing
Protein – derived peptides are presented by MHC (HLA)
membrane proteins – antigen presentation
MHC molecules present both self and non-self protein
– derived peptides
MHC class I molecules are expressed in all nucleated
cells
MHC class II molecules are expressed by professional
antigen presenting cells
ANTIGEN RECOGNITION BY T-CELLS REQUIRES
PEPTIDE ANTIGENS AND ANTIGEN PRESENTING CELLS
THAT EXPRESS MHC MOLECULES
T
Y
soluble Ag
Native
membrane Ag
Cell surface MHCpeptide complex
Peptide
antigen
Cell surface
peptides
No T-cell response
APC
T-cell response
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)
T-cell recognition requires the physical contact of APC and T cell
MHC RESTRICTION OF T-CELL RECOGNITION
TCR
TCR
M HC
MHC
MHC
APC
APC
APC
TCR
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
GENERATION OF MHC CONGENIC MICE
P
Mouse Y
Mouse X
F1
F2
20 times
Mouse X (Y)
Assembly of TCR and BCR
APC
MHC
Antigen
Antigen
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
AKTIVÁCIÓ
CD3
CD3
εδ
s s
s s
εγ
s s
s s
ζζ
s s