19. The Major Histocompatibility Complex Flashcards
1. MHC genes encode proteins that present peptide fragments of proteins to T cells 2. MHC loci are polygenic and polymorphic 3. The variability in HLA molecules determines which pathogens an individual can mount a T cell response to
What is the Major Histocompatibility complex?
- The MHC locus encodes proteins that present peptides to T cells to stimulate an immune response.
- Called the Human Leukocyte Antigen locus in humans
What do MHC molecules do?
They present fragments of peptides to immune cells like T cells to trigger an immune response.
What is the HLA gene loci?
- A complex gene locus with complex organisation.
- Encodes 1 MHC per region and has 3 regions for each class of MHC.
- Other immune genes like the complement are encoded on this loci.
What are the HLA class 1 genes?
HLA-A
HLA-B
HLA-C
What are the HLA class 2 genes?
HLA-DP
HLA-DQ
HLA-DR
These encode both the alpha and beta chains.
What is the structure of MHC class 1?
- 1 polypeptide chain
- 3 domains.
- A1 and A2 domains make up the peptide binding cleft and are made of alpha helices and beta sheets.
- A3 domain is the transmembrane domain and is mainly beta sheets.
- Binds ß2 microglobulin which is needed to stabilise the structure and ensures correct binding to the peptide binding cleft.
What is the structure of MHC class 2?
- 2 polypeptide chains: a and ß
- Each chain has 2 domains: one part of the peptide binding cleft and 1 transmembrane domain.
- A1 and ß1 are the peptide binding domains.
- A2 and ß2 are the transmembrane domains.
What determines what peptide can bind in the peptide binding cleft?
- the shape
- The charge
- The hydrophobicity
What part of the MHC complex does the TCR recognise?
The hypervariable loops at the top of the peptide binding cleft
when would a T cell express both CD8 and CD4?
when they are developing thymocytes in the thymus
What does the MHC TCR interaction need for activation?
The recognition of a co receptor like CD8 or CD4 to stabilise the interaction.
What do CD8 T cells recognise?
The A3 subunit on MHC1.
What do CD4 T cells recognise?
The ß2 subunit on MHC2
What is T cell function restricted by?
MHC activation
What are the functions of CD4 T cells?
- cytokine production
- Macrophage activation
- Help B cell and cytotoxic T cell response.
Where is MHC2 expressed?
On professional antigen presenting cells
1. macrophages
2. Dendritic cells
3. B cells
4. Epithelial cells in the thymus for T cell development
What is the function of CD8 T cells?
Cytotoxic lysis of infected and tumour cells
Where is MHC1 expressed?
On all nucleated cells
Where is the HLA gene loci?
on the P arm of chromosome 6
What are the HLA genes?
- highly polymorphic
- contains >4 million bp and 224 genes
- Contains not just the HLA genes but also genes for proteins involved with antigen processing and presentation
What are the classical HLA class 1 genes?
HLA-A
HLA-B
HLA-C
What are the non classical HLA class 1 genes?
HLA-E
HLA-D
HLA-F
What are some other components of the immune system encoded on the HLA loci?
- The complement
- lymphotoxin
- TNF
- MYC-C
- MYC-B
- Proteasome components like LMP2 and LMP7
What are the classical HLA class 2 genes?
HLA-DP
HLA-DQ
HLA-DR
What antigen processing and presentation genes are encoded on the HLA loci?
- LMP2 and LMP7 that are parts of the proteasome.
- TAP1 and TAP2 which are components of the peptide transporter associated with antigen processing
- TAPBP tapasin - TAP associated protein.
What does the HLA locus composition suggest?
That the whole locus has been selected for processing and presenting antigens to T cells
What kinds of proteins can be presented in MHC class 1?
- Normal proteins
- Old and damaged proteins
- Incorrectly folded proteins
How are peptide loaded into MHC class 1?
- MHC is co-transcriptionally inserted into the ER membrane.
- Associates with chaperone calnexin
- Then Calreticulin stabilises the peptide loading complex.
- Old/damaged/foreign proteins are tagged with ubiquitin for degradation.
- Degraded in the proteasome.
- ER associated amino peptidase trims the peptides so they can fit in the peptide binding groove.
- The peptide is then loaded into the MHC.
- The chaperone calreticulin then releases the complex and a vesicle transports the MHC to the surface for antigen presentation.
How is HLA polygenic?
There are multiple different class 1 and class 2 genes
How is HLA polymorphic?
There are multiple alleles of each gene in the population which serves as a selective advantage to respond to different pathogens.
What is a haplotype?
A set of DNA variations or polymorphisms that tend to be inherited together.
Where is the polymorphism in HLA focused?
- Lots of variation in HLA-A, HLA-B, HLA-C.
- HLA-DR ß also has very focused variation.
- The non classical MHC genes are a lot less variable.
What does the variation in HLA genes cause?
A large number of different HLA molecule structures.
Which are the most variable HLA class 2 proteins?
- HLA-DRß
- HLA-DQß1
- HLA-DPß2
(number indicates the isotype)
Where are the polymorphic amino acids clustered?
- Around the peptide binding cleft
- This changes how the peptide and what peptides bind.
How is there so much variation in the HLA locus?
- Thousands of alleles
- haplotypes of linked genes encode polymorphisms.
- Each person inherits one HLA haplotype from each parent.
- Heterozygote HLA genes are codominantly expressed.
- nearly impossible to find 2 people with the same HLA molecules.
