FUNCTION OF MHC MOLECULES

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

PEPTIDEPEPTIDE

1

3

2

2m

THREE DIMENSIONAL STRUCTURE OF THE MHC CLASS I MOLECULE

EXPRESSED IN ALL NUCLEATED CELLS

2

1

2

1

PEPTIDE

PEPTIDE

EXPRESSED ON PROFESSIONAL ANTIGEN PRESENTING CELLS

THE THREE DIMENSIONAL STRUCTURE OF MHC CLASS II MOLECULES

THE PEPTIDE BINDING SITE OF MHC CLASS I MOLECULES

THE PEPTIDE BINDING SITE OF MHC CLASS II MOLECULES

PEPTIDE

MHC class I accommodate

peptides of 8-10 amino acids

Cleft geometry

MHC class II accommodatepeptides of >13 amino acids

-M

-chain

Peptide

-chain

-chainPeptide

MHCI

P1P2P3P4P5P6P7P8P9Octapeptide

Decapeptide

anchoringamino acids

NH2 COOH

MHCII

P1

NH2

NH2

COOH

COOH

-1 1011-2 P4 P6 P9

anchoringamino acids

Peptides can be eluted from MHC molecules

Acid elute peptides

MHC MOLECULES ARE EXPRESSED 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

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

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

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

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

* * * *

* *

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.

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

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

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

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