Transcript T-cell response

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
REQUIREMENTS FOR ANTIGEN PRESENTATION
1. Expression of MHC molecules
2. ANTIGEN
a) Synthesis of viral antigens - intracellular
b) Uptake of protein antigens – extracellular
3. „Processing” of antigen
generation of peptides suitable for T-cell recognition
4. Presentation of peptides in complex with MHC molecules on the
cell surface
T-cells with  TCR are specialized for recognizing protein –
derived fragments
THE STRUCTURE OF MHC
MEMBERS OF THE IMMUNOGLOBULIN SUPERGENE FAMILY
H
s
s
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L
s
s
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s
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S
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L
MOLECULES CONTAINING ONE
OR MORE Ig DOMAIN(S)
H
s s
s s
V or C domain related
s
s
s s
s s
s s
s s
s s
s s
s s
s s
ss
ss
s s
s s
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Thy-1
IgM
s
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s s
s s
s s
s s
ss
CD79
TCR MHCI
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MHCII ICAM-1 Fc RII
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CD2
g
d
e
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a
b
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CD3
CD4
s s
s s
s s
s s
ss
ss
CD8
CD28
s
s
s
s
s
s
s
s
B-7
Poly-Ig
FUNCTION
RECOGNITION
Ig, TCR, MHC-I, MHC-II
ADHESION
ICAM-1, ICAM-2, VCAM-1,
NCAM
BINDING
CD4, CD8, CD28, B7, IL-1RI,
PDGFR, FcRII, poly-IgR
There are two types of MHC molecule, MHC
class I and MHC class II.
CELL SURFACE EXPRESSION OF MHC ON
VARIOUS CELL TYPES
Szövet
MHC I
MHC II
T cells
B cells
Makrophages
Dendritic cells
+++
+++
+++
+++
+/+++
++
+++
Epithelial cells
+
+++
+++
+
+
+
-
-
Neutrophyls
Hepatocytes
Kidney
Brain
Eritrocytes
Cell surface expression of MHC is influenced by activation
MHC class I molecules are important in immune responses agains viruses
and tumour cells
MHC class II plays a role in the activation of immunocytes and in the
regulation of cell cell cooperation
Genes and proteins of MHC
Some members of the immunoglobulin supergene family
H
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L
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S
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L
EGY VAGY TÖBB Ig DOMÉNT
TARTALMAZÓ FEHÉRJÉK
H
s s
s s
V vagy C doménhez hasonló
s
s
s s
s s
s s
s s
s s
s s
s s
s s
ss
ss
s s
s s
ss
Thy-1
IgM
s
s
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s
s s
s s
s s
s s
ss
CD79
TCR MHCI
s
s
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MHCII ICAM-1 Fc RII
s
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CD2
g
d
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a
b
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s
CD3
CD4
s s
s s
s s
s s
ss
ss
CD8
CD28
s
s
s
s
s
s
s
s
B-7
Poly-Ig
FUNKCTION
RECOGNITION
Ig, TCR, MHC-I, MHC-II
ADHESION
ICAM-1, ICAM-2, VCAM-1,
NCAM
BINDING
CD4, CD8, CD28, B7, IL-1RI,
PDGFR, FcRII, poly-IgR
MHC class I and MHC class II molecules bind
to different T-cell co-receptors.
The structure of MHC proteins
THE PEPTIDE BINDING SITE OF MHC CLASS I
MOLECULES
THE PEPTIDE BINDING SITE OF MHC CLASS II MOLECULES
PEPTIDE
Cleft geometry
-chain
-chain
Peptide
2-M
MHC class I accommodate
peptides of 8-10 amino acids
Peptide
-chain
MHC class II accommodate
peptides of >13 amino acids
The number of different T cell antigen receptors
is estimated to be
1,000,000,000,000,000 (1015)
How can 6 invariant molecules have the capacity to
bind to 1,000,000,000,000,000 different peptides?
Peptides can be eluted from MHC molecules
Acid elute
peptides
Eluted peptides from MHC molecules have different
sequences but contain motifs
Peptides bound to a particular type of MHC class I molecule have
conserved patterns of amino acids
A common sequence in a peptide
antigen that binds to an MHC
molecule is called a MOTIF
N T Y Q R T R L V C
Amino acids common to many peptides
tether the peptide to structural features
of the MHC molecule
ANCHOR RESIDUES
Tethering amino acids need not be
identical but must be related
Y & F are aromatic
V, L & I are hydrophobic
S Y F P E I H
I
K Y Q A V T T L
S Y I P S A K I
R G Y V Y Q Q L
S I
I N F E K L
A P G N Y P A L
Side chains of anchor residues bind
into POCKETS in the MHC molecule
Different types of MHC molecule bind peptides with different patterns
of conserved amino acids
anchoring
amino a cids
anchoring
amino a cids
Decapeptide
NH2 P1
P2 P3
P4 P5 P6
COOH
P7 P8P9
-2
-1 P1
P4
P6
Octapeptide
11
COOH
NH2
COOH
NH2
MHCI
P9 10
MHCII
A flexible binding site?
A binding site that is flexible at an early, intracellular stage of maturation
Formed by folding the MHC molecules around the peptide.
Venus fly trap
Floppy
Compact
Allows a single type of MHC molecule to
• bind many different peptides
• bind peptides with high affinity
• form stable complexes at the cell surface
• Export only molecules that have captured a
peptide to the cell surface
MHC molecules bind peptides according to the following
principals
• Use a small number of anchor residues to tether the peptidethis allows different sequences between anchors
and different lengths of peptide
• Adopt a flexible “floppy” conformation until a peptide binds
• Fold around the peptide to increase stability of the complex
MECHANISM OF ANTIGEN
PRESENTATION
THE ENDOGENOUS AND EXOGENOUS ROUTES OF
ANTIGEN PRESENTATION
Tc
Th
Exogenous Ag
Endogenous
Ag
Endogenous peptides are presented
on MHC I (vírus proteins, tumor
antigens)
Exogenous peptides (toxins, bacterium,
allergen) are presented by MHC II
The MHC I receptor binds the CD8 receptor, while
MHC II binds CD4.
Allelic polymorphism is concentrated in
the peptide antigen binding site
Class I
2
3
1
1
1
2m
2
2
Class II
(HLA-DR)
Polymorphism in the MHC affects peptide antigen binding
Allelic variants may differ by 20 amino acids
Cytosol-derived peptides are
presented by MHCI receptors
Degradation of endogenous proteins in the
(immun)proteosomes
TAP: Transporter associated
With antigen processing
Multiple proteins help Ag presentation
of MHCI
Trimming of antigenic peptides by
ERAP
Presentation of extracellular (Exogen) peptides
bemutatása (MHCII prezentáció)
Invariant chain protects the binding site of
MHCII until it reaches the appropriate
compartment
DMA/DMB
INVARIÁNS LÁNC (Ii)
1. Chaperon – konformáció
2. Peptidkötőhely gátlása
3. Szállító/visszatartó molekula
1. A peptidet befogadó konformáció
fenntartása
2. A CLIP és az exogén fehérjékből
származó peptidek lecserélése
The biological function of MHC
proteins
AZ MHC FUNCTIONS
– Presentation of peptides– self/altered self/foeign peptides
– Continous expression of self-peptidesto monitor cellular health
– Determination of immunological self
• Self MHC + self peptide – individual MHC pluss és saját peptid
• Allogeneic response to fotreign MHC (transplantation)
• Self MHC– autolgous foreign MHC allogeneic activation. Az The
ratio of alloreactive T-cells is very high: 1-10%
– A differentiation and selection of developing thymocytes (in the
thymus)
– promotion of T-limphocyte survival in the priphery
week” tonic” signals induced by MHC / TCR interactions provide
survival signals
– Inhibitory ligands for NK cells, maintainance of host cell integrity.
AZ MHC restriction
T-sejt
T-sejt
TCR
TCR
M HC
MHC
MHC
APC
APC
APC
T-sejt
TCR
TCR/ MHC + peptid complex recognized
A single TCR recognize a single MHC-peptid komplex
The same peptide presented on a different MHC is not recognized.
The same MHC molecule with a different peptide is not recognized by a given TCR
(other TCRs may recognize)
Experiment of Peter DOHERTY & Rolph ZINKERNAGEL
1976
Vírus B
+ Y sejtek
Virus A
T - CELLS
T
T
T
T T
T T
MICE Y
Vírus A
+ Y sejtek
T
T
MICE X
Virus A
+ X cells
Vírus A
+ X cells
T
T
Cells infected with a virus are only killed if the infected cell and virus-specific T
cells are from the same animal or strain. (The MHC needs to be recognized by the
CTL cells ------ MHC restriction ).
Tissue compatibility is encoded by the MHC genes and tissue rejection
requires the presence of T cells
No T cells
MiceY
Thymec
tomy
MiceX
Mice X
No rejection
The MHC locus
MHC protein (HLA)- coding genes
The full sequence and the map of the human MHC locus
HUMAN GENOME PROJECT
3,838,986 bp
224 gene
6 kromoszóma
MHC sequencing
consortium
Nature 401, 1999
http://webace.sanger.ac.uk/cgi-bin/ace/pic/6ace?name=MHC&class=Map&click=400-1
STRUCTURE OF THE MHC
6 kromoszóma rövid karja
MHC
15 kromoszóma
2m
Class II
Class II
DMA/B
21-hydroxilase
C2/C4
LMP TAP
DP
B2 A2 B1 A1
DN
DO
A
B
Klasszikus MHC gének
Class III
POLIMORPHIC
ON PROFESSIONAL APC
C
E
A
G
F
DR
B1 B2 B3 (B4) A
Non- classical MHC genes
E, G, F
I osztály
ALL NUCLEATED CELLLS
HLA – DR, DP, DQ
B
HSP MICA/B
DQ
B2 A2 B1 A1
HLA – Human Leukocyte Antigen system
HLA –A, B, C
TNF
Class I Non polymorphic genes
Class II
Class III
INHERITENCE OF CLASS I AND CLASS II MHC GENES
HUMAN LEUKOCYTE
ANTIGEN
A24
A11
HLA
A1
A2
Ko-domináns öröklésmenet
A24
A2
A24
A1
1.
B27
C1
C6
B8
2.
A11
A1
A11
A2
4.
3.
transz
transz
A24
A1
α1β1
I osztály
EVERY CELL
B8
C1
A24
α2β2
II osztály
PROFESSIONAL APC
a1
b1
a2
b2
cisz
transz
B27
C6
A1
cisz
DQ1
DQ2
POLIMORPHYSM OF MHC IN HUMAN POPULATIONS
A polimorfizmus (allélek) száma
872
CLASS I
1652 allels
~6 x 1015 combinations
506
Frequency (%)
274
A B C
466
CLASS II
688 allels
114
15 25 66
2
     
DR
DP
DQ
Allels
CAU
AFR
ASI
HLA-A1
15.18
5.72
4.48
HLA- A2
28.65
18.88
24.63
HLA- A3
13.38
8.44
2.64
HLA- A28
4.46
9.92
1.76
HLA- A36
0.02
1.88
0.01
In reality allels are not inherited randomy. Allels
are linked, and there must have been strong
selection favoring certain allelic variants. Nonrandom distribution.
Classical MHC genes are inherited as
haplotypes
Parents
DP-1,2
DQ-3,4
DR-5,6
B-7,8
C-9,10
A-11,12
DP
DP
DQ DR
DQ DR
BC
BC
DP-9,8
DQ-7,6
DR-5,4
B-3,2
C-1,8
A-9,10
DP-1,8
DQ-3,6
DR-5,4
B-7,2
C-9,8
A-11,10
A
A
Offspring
X
DP
DQ DR
BC
A
DP
DQ DR
BC
A
DP-1,9
DQ-3,7
DR-5,5
B-7,3
C-9,1
A-11,9
DP-2,8
DQ-4,6
DR-6,4
B-8,2
C-10,8
A-12,10
DP-2,9
DQ-4,7
DR-6,5
B-8,3
C-10,10
A-12,9
DP
DQ DR
BC
A
DP
DQ DR
BC
A
DP
DQ DR
BC
A
DP
DQ DR
BC
A
DP
DQ DR
BC
A
DP
DQ DR
BC
A
DP
DQ DR
BC
A
DP
DQ DR
BC
A
MHC MOLECULES ARE EXPRESSED WITH BOUND PEPTIDES
DERIVED FROM SELF OR NON-SELF PROTEINS
Kidney epithelial cell
B-cell, macrophage,
dendritic cell
Present intra- and extracellular
environment
Liver cell
Present intracellular environment
Class I MHC
Peptides of restricted size, which
derive from cytosolic or
nuclear proteins
Class II MHC
Overlapping peptides of various
sizes, which derive from
membrane proteins
70% derives from MHC molecules
MHC Polimorphysm is maintained by the presence of pathogens
THE OUTCOME OF INFECTION IN A POPULATION
WITH POLYMORPHIC MHC GENES
Example: If MHC X was the only type of MHC molecule
MHC-Gen
MHC
XX
v
v
Pathogen that
evades MHC
X
v
Population threatened
with extinction
V – virus infection
v
v
v
v
v
v
v
v
v
v
v
v
v
v
v
v
v
v
v
v
v
v
Population is protected