The major histocompatibility complex

Question 1

a) overview of MHCI and II
b) structure of MHCI and II

Answer 1

a) MHC is a genetic locus on chromosome 6 that encodes MHC class I and class II genes and other molecules involved in antigen processing pathways. They were initially identified due to rejection of transplanted tumours. They are associated with susceptibility and resisitance to infection and disease
b) Both very similar as they both interact with T cells. MHC class I is made up of a heavy chain (α1, α2, α3 domains) and a light chain (β₂m domain). MHC class II is made up of an α chain (α1and α2 domains), and a β chain (β1 and β2 domains). (see image)

Question 2

a) Binding of cytotoxic T cell to MHCI
b) Binding of T helper cell to MHCII

Answer 2

a) TCR must detect both the peptide and the MHCI. CD8α and CD8β chains of the cytotoxic T cell detect the α3 chain of MHCI, hence restricting its binding to this MHC
b) Again, TCR must detect both peptide and MHCII. CD4 chain of T helper cell detects β2 chain of MHCII, hence restricting its binding to this MHC

Question 3

a) four ways that MHC molecules are diverse
b) diversity due to polygeny

Answer 3

a) Polygeny. Polymorphism. Inheritance of MHC halpotypes. Peptide binding properties of MHC molecules
b) There are three related MHC class I loci, which code for the heavy chain - HLA-A, HLA-B and HLA-C
There are three related MHC class II loci, which code for the α chain and the β chain - HLA-DP, HLA-DQ and HLA-DR
(HLA - human leukocyte antigen, same as MHC)

Question 4

Diversity due to polymorphism

Answer 4

There are many alleles at each loci (allelic polymorphism), with 9,341 protein variants. Many amino acid changes. Co-dominant expression, so individuals will express unique combinations of allels. Polymorphism benefits the individual and the population, as some individuals will be better equipped. Polymorphism is ancient and pathogen driven (exposure to the pathogen means that useful MHC will be expressed in the population). Alleles may be associated with disease susceptibility.

Question 5

Diversity due to inheritance as haplotypes

Answer 5

MHC loci are closely linked. The genes are inherited together as haplotypes. Recombination generates new combinations of alleles (haplotypes) to be tested for beneficial/adverse effects (most of the time haplotypes are passed on to the offspring, but in 3% births there are new combinations of alleles)

Question 6

a) where is polymorphism concentrated?
b) promiscuous presentation (evidence polymorphism is pathogen driven)

Answer 6

a) In the peptide binding domain. Variation allows different peptides to bind different alleles. The TCR sees a combination of MHC and peptide (MHC restriction). It is very unusual for a TCR to be able to see the same peptide presented by a different MHC allele.
b) Seen in chickens, as they have a single dominantly expressed MHC class I molecule (chicken single fastidious or chicken single promiscuous). The single fastidious haplotype confers either protection or susceptibility against a pathogen, and the fastidious class I allele either does or does not find a protective peptide. The single promiscuous haplotype confers more or less protection against most pathogens, and the promiscuous class I allele finds a protective peptide.
Promiscuous binders survive, whilst fastidious die, as they are unable to present a protective peptide when exposed to a pathogen, so die.

Question 7

Features of MHC peptide interaction

Answer 7

In the absence of infection, MHC molecules are occupied by self peptides. Peptide presentation requires a balance of promiscuous and fastidious binding - i) if a large number of different peptides can bind (promiscuous), only a few copies of any particular peptide-MHC combination will be presented at the cell surface ii) if a small number of different peptides can bind (fastidious), many copies of the same peptide-MHC will be presented at the surface, however, pathogens with a small genome may not have a suitable peptide for presentation by the host’s MHC molecules. Typically a cell with 100,000 MHC class I molecules of a single allotype will present >1000 different peptides. Individual peptide-MHC complexes may be present at roughly 1-5000 molecules per cell (mean of 100). T cells may be able to be activated by a single peptide-MHC complex, making them very sensitive, or up to a few thousand

Question 8

MHC class I processing pathway

Answer 8

See image

Question 9

MHC class II processing pathway

Answer 9

See image