Lecture 4- Major Histocompatibility Complex and recognition by T cells

Question 1

How are T-cells made?

Answer 1

They are made in the bone marrow. Then migrate to the thymus. In thymus they differentiate into mature T cells. Then they can go into lymphoid tissue and function. Thymus is behind the lungs above the heart.

Question 2

How does the T cell develop in the thymus?

Answer 2

It either becomes the CD8 T cell or the CD4 T cell.

CD8= cytotoxic T cell. CD4= helper T cell (Th)

Question 3

What happens to the thymus as we age?

Answer 3

As we age, the thymus shrinks. (involution)

Thymic function reduces as we get older.

Question 4

What does the T cell receptor look like?

Answer 4

If you take the fab fragment of the b cell receptor (antibody) off. It looks like the t cell receptor.

Question 5

How are TCRs specific?

Answer 5

TCR Valpha and Vbeta domains contain hyper variable regions resulting in different Complementarity Determining Regions (CDRs) on different T cell, specific for different antigen epitopes

Question 6

What is CD3?

Answer 6

CD3 is associated with TCR.
Not involved in antigen recognition.
Interacts with TCR to mediate intracellular signalling.

Question 7

How do TCR recognise antigen?

Answer 7

TCRs do not recognise antigen directly (unlike antibody & BCRs).
Antigen has to be processed and presented to them via the Major Histocompatibility Complex (MHC).

Question 8

What is the MHC?

Answer 8

Major histocompatibility complex (MHC): collection of genes arrayed within a long continuous stretch of DNA.
In chromosome 6 in human and chromosome 17 in mice.
In human called HLA complex (Human Leukocyte Antigen).

Question 9

How are mhc genes arranged?

Answer 9

Major histocompatibility complex (MHC): collection of genes arrayed within a long continuous stretch of DNA.

MHC genes are organised into regions encoding three classes of molecules:

MHC class I
MHC class II
MHC class III

Question 10

MHC class I

Answer 10

Cell surface glycoproteins expressed on all nucleated cells.
Involved in T cell recognition of antigen (Tc). for t cytotoxic cells.
MHC I encoded by the A, B & C loci in humans.

Question 11

MHC class II

Answer 11

More restricted to certain cells than class I.
Cell surface glycoproteins expressed on antigen presenting cells (eg. Macrophages, dendritic cells and B-cells).
Involved in T cell recognition of antigen (TH). T helper cells.
MHC I encoded by the DP, DQ and DR regions in humans.

Question 12

MHC class III

Answer 12

Code for Various proteins with or without immune function, including:
Components of complement
Tumour necrosis factor
Heat shock proteins

Not involved in recognition of T cell, even though sit right next to them.

Question 13

Which MHC classes are involved in antigen presenting to the t cells?

Answer 13

Only class I and class II

Question 14

Difference in structure between MHC class I and class II?

Answer 14

Class I- alpha chain has 3 domains. Then separate chain making up 4th domain called microglobulin beta. Only one transmembrane domain.

Class II- alpha chain has 2 domains. Beta chain has 2 domains. Both chains have transmembrane and cytoplasmic domains.
Their binding clefts are very similar between these classes.

Question 15

How are HLA inherited?

Answer 15

1 gene from mother and 1 from father. Co-dominant.

Both expressed.

Question 16

What are the functions of class I and class II MHC?

Answer 16

MHC class I and II are highly specialised antigen-presenting molecules that form complexes with peptide ligands.

Class I and class II molecules exhibit polymorphisms in the region that binds peptide.

Any one individual expresses only a small number of these proteins: up to 6 for MHC-I and upt to 12 for MHC-II.

Question 17

What sized peptides can class I and II MHC accommodate?

Answer 17

Class I has smaller cleft, can only accommodate small peptides 8-10 amino acids. 
class II bigger, can accommodate peptides bigger than 13 amino acids.

Question 18

Another important difference between class I and II mhc?

Answer 18

Class I MHC: involved in presentation of intracellular antigens, eg viral.

Class II MHC is involved in presentation of extracellular antigens eg worm, some bacteria

Question 19

What are the steps of the MHC I processing endogenous antigen? (intracellular antigen)

Answer 19

1. The antigen is in the cytoplasm.
2. The cell will recognise there is something wrong and take the antigen to a complex called the proteosome which breaks it down.
3. This degradation produces antigen peptides. These are transported into the RER by a transporter called TAP.
4. The class I MHC is in the ER. It is associated with p88/calnexin in the ER usually. But when the antigen peptides enter the ER and bind, the calnexin dissociates. and the peptide can be loaded into the MHC.
5. The MHC gets into a secretory vesicle and fuses with the membrane so you have the receptor on the cell surface.

Question 20

What are the steps of the MHC II processing exogenous antigen?

Answer 20

1. The cell encounters a bacteria or an extracellular antigen that shouldn’t be there. The cell endocytoses it.
2. The endosome fuses with the lysosome to cleave the antigen and give antigen peptides.
3. Class II made in RER. Also bound to a protein that keeps it in check- called the invariant chain. It’s partially bound to the cleft so stops peptide getting in cleft.
4. The class II MHC is loaded into a secretory vesicle and this fuses with the endolysosome where the peptide is.
5. The endolysosome degrades the invariant chain so it lets go of the MHC and the peptide can bind to the cleft.
6. So the MHC and peptide then goes to the surface and is presented on surface.

Question 21

What happens once the MHC presents the antigen on a cell?

Answer 21

The TCR can now bind. It binds to both the antigen peptide and MHC. The TCR needs the right antigen as well as the right MHC to recognise.

Question 22

What other membrane receptors are important for the recognition and signalling?

Answer 22

CD4: recognize antigen combined with class II MHC 
CD8: recognize antigen combined with class I MHC

(remember we have cd4 or cd8 t cells)
These increase the strength of the binding between TCR and MHC-antigen peptide complex.

Question 23

How do cd4 and cd8 strengthen binding?

Answer 23

CD8 binds the alpha3 domain of MHC class I
CD4 binds the Beta2 domain of MHC class II

Question 24

What are the advantages of MHC-associated recognition

Answer 24

1. Extra recognition mechanism for pathogen to try to evade
2. Recognising different parts of pathogen from antibody
3. Some peptides are from functional parts of protein (eg essential enzyme sequences)
4. Can detect antigen that is inside cells (ie CD8 T cell detecting Class I MHC-associated peptides)
5. Less scope for mutations in pathogens to avoid recognition