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T-LYMPHOCYTES RECOGNIZE ANTIGEN-DERIVED PROTEIN FRAGMENTS (PEPTIDES) EXPRESSED ON THE SURFACE OF SELF
ANTIGEN PRESENTING CELLS
VIRUS-INFECTED CELLS ARE RECOGNIZED BY T-LYMPHOCYTES IN MHC-DEPENDENT MANNER
TISSUE TRANSPLANTATION IS RESTRICTED BY MHC MOLECULES
THE IMMUNE RESPONSE TO PROTEIN ANTIGENS IS REGULATED BY INDIVIDUALLY POLYMORPHIC MHC GENES
ANTIGEN PRESENTING CELLSANTIGEN PRESENTING CELLS
Synthesize antigens – endogenous antigensendogenous antigens (virus, tumor)
Internalize antigens – exogenous antigensexogenous antigens (any protein)
Degrade protein antigens to peptides – processingprocessing
Protein – derived peptides are presented by MHC (HLA) membrane proteins – antigen presentationantigen presentation
MHC molecules present both self and non-self protein MHC molecules present both self and non-self protein – derived peptides– derived peptides
MHC class I molecules are expressed in all nucleated MHC class I molecules are expressed in all nucleated cellscells
MHC class II molecules are expressed by professional MHC class II molecules are expressed by professional antigen presenting cellsantigen presenting cells
ANTIGEN RECOGNITION BY T-CELLS REQUIRESPEPTIDE ANTIGENS AND ANTIGEN PRESENTING CELLS
THAT EXPRESS MHC MOLECULES
YT
No T-cell response
soluble Ag
Native membrane Ag
Peptide antigen
Cell surface MHC-peptide complex
T-cell response
Cell surfacepeptides APC
THE STRUCTURE OF MHC GENES AND PROTEINS
s s
s s
s
s
s s
ss s
s s
s
s
s s
s
s ss s
s
s
s
s
s
s
s
s
s ss s
L
H HL
s ss s
s ss s
ss
s
s
s
s
ss
s
s
s
s
s
s
ssss
gde
ss
ss
a b
s
s
s
s
ss
s
s
s
s
s
s
ss
ss
s
s
s
s
s
s
ss
s
s
s
s
IgM CD79 TCR MHCI MHCIIThy-1 ICAM-1
CD2 B-7CD28CD8CD4CD3
ss
ss
s s
Fc RII
Poly-Ig
MEMBERS OF THE IMMUNOGLOBULIN SUPERGENE FAMILY
FUNCTION
RECOGNITION
Ig, TCR, MHC-I, MHC-II
ADHESION
ICAM-1, ICAM-2, VCAM-1, NCAM
BINDING
CD4, CD8, CD28, B7, IL-1RI, PDGFR, FcRII, poly-IgR
MOLECULES CONTAINING ONE OR MORE Ig DOMAIN(S)
V or C domain related
COOHNH2
TM CCOOHNH2
MHC class II
TM
NH2NH2
COOHCOOH
HOOCC
COOHNH2 COOHNH2
TM C
Transmembrane region (TM)
Cytoplasmic region ©
– carbohydrate
NH2
Peptide binding site
MHC class II
THE STRUCTURE OF MHC GENE PRODUCTS
3 2m
2
1 1
2 2
1
1 2 3 1 2 1 2
3 and 2m Ig supergene family 2 and 2
3,838,986 bp224 genes
on chromosome 6
http://webace.sanger.ac.uk/cgi-bin/ace/pic/6ace?name=MHC&class=Map&click=400-1
The MHC sequencing consortium
Nature 401, 1999
MAP OF THE HUMAN MHC FROM THE HUMAN GENOME PROJECT
TNF
LMP TAP
21-hydroxilase
Class III Non polymorphic genesClass II Class I
E G F
HSP
Class II
DMA/B
MICA/B
B C A
C2/C4
DQDP DN DR
B2 B2 B2A2 A2 B3B1 B1 (B4)A1 A1 AB B1A
DO
Classical MHC genes POLYMORPHIC
HLA – Human Leukocyte Antigen
HLA –A,B, C class I
EXPRESSED IN ALL NUCLEATED CELLS
HLA – DR, DP, DQ class II
EXPRESSED IN PROFESSIONAL APC
Non- classical MHC genes
E, G, F
Chromosome 6 short arm MHC
Chromosome 15 2m
LOCALIZATION OF MHC GENES
Class III genes
Differential distribution of MHC molecules
Tissue MHC class I MHC class II
T cells +++ +/-B cells +++ +++Macrophages +++ ++Other APC +++ +++
Epithelialcells of thymus + +++
Neutrophils +++ -Hepatocytes + -Kidney + -Brain + -Erythrocytes - -
Cell activation affects the level of MHC expressionThe pattern of expression reflects the function of MHC molecules
Class I is involved in anti-viral immune responsesClass II involved in activation of other cells of the immune system
A24A1
A24A11
A1A2
A11A2
A11A1
A24A2
1. 2. 3. 4.
INHERITANCE OF MHC CLASS I AND CLASS II GENES
HUMAN LEUKOCYTE ANTIGEN
HLA
α1β1 α2β2
PROFESSIONAL APC
transz
A24
A24
C1
C1
B8
B8
B27
B27
C6
C6
A1
A1
b2b1a1
transz
a2
DQ1cisz
cisz
transz
DQ2
EVERY CELL
CLASS ICLASS II
EVERY CELL
CLASS ICLASS II
POSTULATION
• every individual has 6 MHC class I molecules• alleles of all MHC types are distributed randomly in the population• every one of the 1 200 different alleles can be expressed with any
other allele
POLYMORPHISM OF MHC MOLECULES IN THE HUMAN POPULATION
~6 x 1015 individual combinations
Only monozygous twins are identical at the HLA locus
The human population is extensively outbred
MHC genetics in humans is extremely complex
PPOOLYGENIC & POLYMORPHICLYGENIC & POLYMORPHIC
Alleles are not distributed evenly in the population
Alleles are segregated among races
SELECTION
15.18
28.65
13.38
4.46
0.02
5.72
18.88
8.44
9.92
1.88
4.48
24.63
2.64
1.76
0.01
CAU AFR ASI
Frequency (%)
HLA-A1
HLA- A2
HLA- A3
HLA- A28
HLA- A36
Allelic groups
A B C
Po
lym
orp
his
m (
nu
mb
er o
f al
lele
s) Class I
657 alleles185
91
381
Class II492 alleles
2
317
1989
2045
DR DP DQ
DISTRIBUTION OF MHC ALLELES IN THE HUMAN POPULATION
Inheritance of MHC haplotypes
B C ADP DQ DR
B C ADP DQ DR
B C ADP DQ DR
B C ADP DQ DR
X
ParentsDP-1,2DQ-3,4DR-5,6B-7,8C-9,10A-11,12
DP-9,8DQ-7,6DR-5,4B-3,2C-1,8A-9,10
DP-1,8DQ-3,6DR-5,4B-7,2C-9,8A-11,10
DP-1,9DQ-3,7DR-5,5B-7,3C-9,1A-11,9
DP-2,8DQ-4,6DR-6,4B-8,2C-10,8A-12,10
DP-2,9DQ-4,7DR-6,5B-8,3C-10,10A-12,9
B C ADP DQ DR
B C ADP DQ DR
B C ADP DQ DR
B C ADP DQ DR
B C ADP DQ DR
B C ADP DQ DR
B C ADP DQ DR
B C ADP DQ DR
Children
FUNCTIONS OF MHC MEMBRANE PROTEINS
PEPTIDE
1
3
2
2m
STRUCTURE OF CLASS I MHC MOLECULES
EXPRESSED BY ALL NUCLEATED CELLS
2
1
2
1
PEPTIDE
EXPRESSED BY PROFESSIONAL ANTIGEN PRESENTING CELLS
CAN BE INDUCED IN OTHER CELLS (endothel, microglia, astocyte)
STRUCTURE OF CLASS II MHC MOLECULES
MEMBRANE RECEPTORSMEMBRANE RECEPTORS
Intracellular peptide binding Intracellular peptide binding capacitycapacity
One binding site can One binding site can accomodate multiple peptidesaccomodate multiple peptides
MHC – PEPTIDE COMPLEXESMHC – PEPTIDE COMPLEXES
1
3
2
2m 2
1
2
1
Allelic polymorphism is concentrated inthe peptide antigen binding site
Polymorphism in the MHC affects peptide antigen binding
Allelic variants may differ by 20 amino acids
Class II(HLA-DR)
Class I
MHC class I accommodatepeptides of 8-10 amino acids
Cleft geometry
MHC class II accommodatepeptides of >13 amino acids
-M
-chain
Peptide
-chain
-chainPeptide
DPB1*01011 TAC GCG CGC TTC GAC AGC GAC GTG GGG GAG TTC CGG GCG GTG ACG GAG CTG GGG CGG CCT GCT GCG GAG TAC TGG AAC AGC CAG AAG GAC ATC CTG GAG GAG DPB1*01012 --- --- --- --- --- --- --- --- --A --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*02012 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*02013 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -AC -A- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*0202 CT- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -AG --- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*0301 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --C --- --- --- --- --- --- --- C-- --- --- --- DPB1*0401 -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*0402 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*0501 CT- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -AG --- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*0601 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --C --- --- --- --- --- --- --- C-- --- --- --- DPB1*0801 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*0901 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --C --- --- --- --- --- --- --- --- --- --- --- DPB1*1001 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*11011 --- --- --- --- --- --- --- --- --A --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- C-- --- --- --- DPB1*11012 --- --- --- --- --- --- --- --- --A --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- C-- --- --- --- DPB1*1301 --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*1401 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --C --- --- --- --- --- --- --- C-- --- --- --- DPB1*1501 --- --- --- --- --- --- --- --- --A --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- C-- --- --- --- DPB1*1601 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*1701 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --C --- --- --- --- --- --- --- --- --- --- --- DPB1*1801 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*1901 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -AG --- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*20011 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --C --- --- --- --- --- --- --- C-- --- --- --- DPB1*20012 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --C --- --- --- --- --- --- --- C-- --- --- --- DPB1*2101 CT- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -AG --- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*2201 CT- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -AG --- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*2301 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*2401 -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -AG --- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*2501 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --- --- --- --- --- --- --- --- C-- --- --- --- DPB1*26011 --- --- --- --- --- --- --- --- --A --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*26012 --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- ---
30 HLA-DP allele sequences betweenNucleotides 204 and 290
(amino acids 35-68)
Most polymorphisms are point mutations
Y-F A-V Silent A-D A-EE-A
I-L
Polymorphic nucleotides encode amino acids associated with the peptide binding site
MHCI
P1P2P3P4P5P6P7P8P9Octapeptide
Decapeptide
anchoringamino acids
NH2 COOH
MHCII
P1
NH2
NH2
COOH
COOH
-1 1011-2 P4 P6 P9
anchoringamino acids
STRUCTURE OF THE PEPTIDE BINDING SITESTRUCTURE OF THE PEPTIDE BINDING SITE
P2 & P9 interact with hydrophobic pockets
Amino acid side chains of the ‘core’ region occupy evenly distributed pockets
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
P E IYS F H I
A V TYK Q T L
P S AYS I K I
R T RYT Q L VN C
Tethering amino acids need not be identical but must be related
Y & F are aromaticV, L & I are hydrophobic
Side chains of anchor residues bind into POCKETS in the MHC molecule
S I I FN E K L
A P G YN P A L
R G Y YV Q Q L
Different types of MHC molecule bind peptides with different patterns of conserved amino acids
A common sequence in a peptide antigen that binds to an MHC molecule is called a MOTIF
Amino acids common to many peptides tether the peptide to structural features
of the MHC moleculeANCHOR RESIDUES
PEPTIDE MOTIFS IN SELF AND FOREIGN PROTEINSPEPTIDE MOTIFS IN SELF AND FOREIGN PROTEINS
MHC MOLECULES ARE EXPRESSED IN THE CELL SURFACE MEMBRANE WITH BOUND PEPTIDES DERIVED FROM SELF OR NON-
SELF PROTEINS
B-cell, macrophage, dendritic cell
Kidney epithelial cell
Liver cell
Present intracellular environment
Present intra- and extracellular environment
Class I MHC – code of 6Immunological ID
Peptides of restricted size, which derive from cytosolic or nuclear
proteins
Class II MHC
Overlapping peptides of various sizes, which derive from
membrane/exogeneous proteins
70% derives from MHC molecules
BENEFITS OF MHC POLYMORPHISM IN THE POPULATIONBENEFITS OF MHC POLYMORPHISM IN THE POPULATION
A DQB1DRB1Loci:
Person 1 Person 2
Haplotype
Alle
les
Alle
les
Gen
etic
pol
ymor
hism
of t
he p
opul
atio
n
Gen
otyp
e
Haplotype
21
2625
23113
271813
7
743
1824 2 3
B
138
32
113735
18
32
321
271 4 1
38 987
A DQB1DRB1
2
1
24
23
25
38
37
27
18
13
4
3
2
3511
3
2
1
1 3
B
138
32
113735
18
3
21
271 3 21
38 874
39
COMBINATION OF MHC ALLOTYPES IN INDIVIDUALS AND IN THE POPULATION
* * * *
* *
Populations need to express variantsof each type of MHC molecule
• The rate of replication by pathogenic microorganisms is faster than human reproduction
• In a given time a pathogen can mutate genes more frequently than humans and can easily evade changes in MHC molecules
• The number of types of MHC molecules are limited
To counteract the flexibility of pathogens
• The MHC has developed many variants of each type of MHC molecule
• These variants may not necessarily protect all individuals from every pathogen, but will protect the population from extinction
THE OUTCOME OF INFECTION IN A POPULATION WITH POLYMORPHIC MHC GENES
MHC-GenMHC-Gen
vv
vv
vv
v
vv
v
v
v
v
v v v
v
vv
v
vv
v
vv
Example: If MHC X was the only type of MHC molecule
Population threatenedwith extinction
Pathogen that evades MHC
X
MHCXX
Population is protected
Molecular basis of MHC types and variants
POLYMORPHISMVariation >1% at a single genetic locus in a
population of individualsMHC genes are the most polymorphic known
The type and variant MHC molecules do not vary in the lifetime of the individual
The diversity in MHC molecules exists at the population levelThis sharply contrast diversity in T and B cell antigen receptors which
exists within the individual
POLYGENISM
Several MHC class I and class II genes encoding different types of MHC molecule
with a range of peptide-binding specificities.
Foreign peptidesForeign peptides
Peptides Peptides recognized by an recognized by an
individualindividual
CHANGES OF GENETIC POLYMORPHISM IN THE POPULATIONCHANGES OF GENETIC POLYMORPHISM IN THE POPULATION
Multiple heterozygous alleleMultiple heterozygous allele
HomozygousHomozygous
FUNCTIONS OF MHC
• CLASSICAL MHC GENE PRODUCTS– Presentation of peptides derived from self proteins – continuos presentation
of self for the immune system– Determination of immunological self
• Self MHC + self peptides– Presentation of peptides derived from foreign (antigenic) proteins– Determination of non-self
• Self MHC + non-self peptides– Allogeneic immune response against non-self MHC (transplantation)
• Recognition of non-self MHC + peptide combinations – consequence of MHC-restricted T-cell recognition
– NK cell recognition– T-lymphocyte differentiation and selection in the thymus– T-lymphocyte survival in the periphery
• NON CLASSICAL MHC GENES– Specialized functions
• PROTEINS STRUCTURALLY RELATED TO CLASSICAL MHC MOLECULES
OTHER GENES IN THE MHC – not polymorphicMHC Class 1b genes
Encoding MHC class I-like proteins that associate with -2 microglobulinRestricted tissue expression
HLA-G trophoblast, interacts CD94 (NK-cell receptor). Inhibits NK cell attack of foetus/ tumours
HLA-E in the membrane of certain cells, binds conserved leader peptides from HLA-A, B, C. Interacts with CD94
HLA-F fetal liver, eosinophil surface, function unknown
MHC Class II genesEncoding several antigen processing genes
HLA-DMand in professional APC, proteasome components (LMP-2 & 7), peptide transporters (TAP-1 & 2), HLA-DO and DO
Many pseudogenes
MHC Class III genesEncoding complement proteins C4A and C4B, C2 and FACTOR B
TUMOUR NECROSIS FACTORS-
Immunologically irrelevant genesGenes encoding 21-hydroxylase, RNA Helicase, Caesin kinase
Heat shock protein 70, Sialidase