Lecture 12 - MHC : Antigen Processing and Presentation

Question 1

What is the MHC?

Answer 1

“MHC” = Major Histocompatability Complex
Gene cluster identified for role in transplant rejection
Encodes MHC class I and MHC class II proteins (and others)
MHC class I expressed by all nucleated cells
MHC class II expressed by Antigen Presenting Cells (APCs)
MHC protein main role = “presenting” short peptides on cell surface
MHC-peptide is recognised by T cells via TCR
MHC class I presents peptides derived from cytosolic proteins to CD8 Tc cells (e.g. antigens from viruses)
MHC class II presents peptides derived from proteins in intracellular vesicles to CD4 Th cells (e.g. antigens from extracellular pathogens)

Question 2

Describe MHC-TCR interaction

Answer 2

TCR interacts simultaneously with both MHC + associated peptide (compound ligand)
i.e. “TCR recognises peptide in the context of MHC”
So T cells only activated if peptide is presented by MHC
T cell recognises all this through receptor - recognises peptide presented by MHC - free peptide will not activate a T cell
Receptor binds to both peptide and MHC requires interaction with both

Question 3

Describe MHC polygeny

Answer 3

Polygenic = Every person expresses several different variants
Human MHC gene cluster on chromosome 6
Human MHC genes = Human Leukocyte Antigen genes (HLA)
Each person expresses 3x different MHC class I α chain genes
(i.e. HLA-A; HLA-B; HLA-C) from each chromosome 6
Each person expresses 3x different MHC class II α+β chain genes
(i.e. HLA-DP; HLA-DQ; HLA-DR) from each chromosome 6

Question 4

Describe MHC polymorphism

Answer 4

Polymorphic = Human population contains many different variants (alleles)
MHC genes are the most polymorphic genes known
i.e. human population contains large number distinct variants / alleles
Each variant ~ equally common in human population
Everyone likely has different variants on each chromosome (diploid)
2x chromosome * 3x HLA per chromosome = 6x MHC per person
The genes have single amino acid changes with large consequences so MHC proteins bind to different peptides
Large variation in MHC clusters
Allelic variation localises to peptide-binding groove:
Polymorphisms alter shape of peptide-binding groove
Altered shape means different variants bind different peptides
Peptides bind to particular MHCs through “ANCHOR RESIDUES”
MHC polymorphisms greatest in peptide-binding groove
Peptide anchor residues fit into pockets formed by polymorphisms
So different MHC molecules bind different peptides
i.e. difficult for pathogens to evolve to be “non-presentable”