19. The Major Histocompatibility Complex

Question 1

What is the Major Histocompatibility complex?

Answer 1

1. The MHC locus encodes proteins that present peptides to T cells to stimulate an immune response.
2. Called the Human Leukocyte Antigen locus in humans

Question 2

What do MHC molecules do?

Answer 2

They present fragments of peptides to immune cells like T cells to trigger an immune response.

Question 3

What is the HLA gene loci?

Answer 3

1. A complex gene locus with complex organisation.
2. Encodes 1 MHC per region and has 3 regions for each class of MHC.
3. Other immune genes like the complement are encoded on this loci.

Question 4

What are the HLA class 1 genes?

Answer 4

HLA-A
HLA-B
HLA-C

Question 5

What are the HLA class 2 genes?

Answer 5

HLA-DP
HLA-DQ
HLA-DR

These encode both the alpha and beta chains.

Question 6

What is the structure of MHC class 1?

Answer 6

1. 1 polypeptide chain
2. 3 domains.
3. A1 and A2 domains make up the peptide binding cleft and are made of alpha helices and beta sheets.
4. A3 domain is the transmembrane domain and is mainly beta sheets.
5. Binds ß2 microglobulin which is needed to stabilise the structure and ensures correct binding to the peptide binding cleft.

Question 7

What is the structure of MHC class 2?

Answer 7

1. 2 polypeptide chains: a and ß
2. Each chain has 2 domains: one part of the peptide binding cleft and 1 transmembrane domain.
3. A1 and ß1 are the peptide binding domains.
4. A2 and ß2 are the transmembrane domains.

Question 8

What determines what peptide can bind in the peptide binding cleft?

Answer 8

1. the shape
2. The charge
3. The hydrophobicity

Question 9

What part of the MHC complex does the TCR recognise?

Answer 9

The hypervariable loops at the top of the peptide binding cleft

Question 10

when would a T cell express both CD8 and CD4?

Answer 10

when they are developing thymocytes in the thymus

Question 11

What does the MHC TCR interaction need for activation?

Answer 11

The recognition of a co receptor like CD8 or CD4 to stabilise the interaction.

Question 12

What do CD8 T cells recognise?

Answer 12

The A3 subunit on MHC1.

Question 13

What do CD4 T cells recognise?

Answer 13

The ß2 subunit on MHC2

Question 14

What is T cell function restricted by?

Answer 14

MHC activation

Question 15

What are the functions of CD4 T cells?

Answer 15

1. cytokine production
2. Macrophage activation
3. Help B cell and cytotoxic T cell response.

Question 16

Where is MHC2 expressed?

Answer 16

On professional antigen presenting cells
1. macrophages
2. Dendritic cells
3. B cells
4. Epithelial cells in the thymus for T cell development

Question 17

What is the function of CD8 T cells?

Answer 17

Cytotoxic lysis of infected and tumour cells

Question 18

Where is MHC1 expressed?

Answer 18

On all nucleated cells

Question 19

Where is the HLA gene loci?

Answer 19

on the P arm of chromosome 6

Question 20

What are the HLA genes?

Answer 20

1. highly polymorphic
2. contains >4 million bp and 224 genes
3. Contains not just the HLA genes but also genes for proteins involved with antigen processing and presentation

Question 21

What are the classical HLA class 1 genes?

Answer 21

HLA-A
HLA-B
HLA-C

Question 22

What are the non classical HLA class 1 genes?

Answer 22

HLA-E
HLA-D
HLA-F

Question 23

What are some other components of the immune system encoded on the HLA loci?

Answer 23

1. The complement
2. lymphotoxin
3. TNF
4. MYC-C
5. MYC-B
6. Proteasome components like LMP2 and LMP7

Question 24

What are the classical HLA class 2 genes?

Answer 24

HLA-DP
HLA-DQ
HLA-DR

Question 25

What antigen processing and presentation genes are encoded on the HLA loci?

Answer 25

1. LMP2 and LMP7 that are parts of the proteasome.
2. TAP1 and TAP2 which are components of the peptide transporter associated with antigen processing
3. TAPBP tapasin - TAP associated protein.

Question 26

What does the HLA locus composition suggest?

Answer 26

That the whole locus has been selected for processing and presenting antigens to T cells

Question 27

What kinds of proteins can be presented in MHC class 1?

Answer 27

1. Normal proteins
2. Old and damaged proteins
3. Incorrectly folded proteins

Question 28

How are peptide loaded into MHC class 1?

Answer 28

1. MHC is co-transcriptionally inserted into the ER membrane.
2. Associates with chaperone calnexin
3. Then Calreticulin stabilises the peptide loading complex.
4. Old/damaged/foreign proteins are tagged with ubiquitin for degradation.
5. Degraded in the proteasome.
6. ER associated amino peptidase trims the peptides so they can fit in the peptide binding groove.
7. The peptide is then loaded into the MHC.
8. The chaperone calreticulin then releases the complex and a vesicle transports the MHC to the surface for antigen presentation.

Question 29

How is HLA polygenic?

Answer 29

There are multiple different class 1 and class 2 genes

Question 30

How is HLA polymorphic?

Answer 30

There are multiple alleles of each gene in the population which serves as a selective advantage to respond to different pathogens.

Question 31

What is a haplotype?

Answer 31

A set of DNA variations or polymorphisms that tend to be inherited together.

Question 32

Where is the polymorphism in HLA focused?

Answer 32

1. Lots of variation in HLA-A, HLA-B, HLA-C.
2. HLA-DR ß also has very focused variation.
3. The non classical MHC genes are a lot less variable.

Question 33

What does the variation in HLA genes cause?

Answer 33

A large number of different HLA molecule structures.

Question 34

Which are the most variable HLA class 2 proteins?

Answer 34

1. HLA-DRß
2. HLA-DQß1
3. HLA-DPß2
   (number indicates the isotype)

Question 35

Where are the polymorphic amino acids clustered?

Answer 35

1. Around the peptide binding cleft
2. This changes how the peptide and what peptides bind.

Question 36

How is there so much variation in the HLA locus?

Answer 36

1. Thousands of alleles
2. haplotypes of linked genes encode polymorphisms.
3. Each person inherits one HLA haplotype from each parent.
4. Heterozygote HLA genes are codominantly expressed.
5. nearly impossible to find 2 people with the same HLA molecules.