Lecture 3

Question 1

what are the features of the TCR alpha chain?

Answer 1

V region genes and J region genes
random joining of the DNA
a particular V region joins to a particular J region, but then is spliced to form rearranged DNA - alpha constant region.
the alpha constant region encodes for the TCR alpha chain

Question 2

what are the features of the TCR beta chain?

Answer 2

D and J regions combine, followed by the additional combination of a V region.
results in a V, D and J region.
this is then spliced onto the constant region of the TCR beta chain

Question 3

where does TCR recognise Ag?

Answer 3

in the groove of MHC molecules

Question 4

how are MHC molecules co-dominantly expressed?

Answer 4

a single person will have up to 12 different MHC molecules
MHC molecules are very polymorphic - they have many alleles
if heterozygous at each loci, one person can express six different class I molecules - similarly for MHC class II

Question 5

what are the advantages for high levels of MHC polymorphism?

Answer 5

allows the binding of a vast range of peptides that can be presented to T cells –> provides a clear evolutionary advantage to the population

Question 6

what is the downside of MHC being highly polymorphic?

Answer 6

increases risk of many immune-mediated disease e.g. autoimmune diseases (i.e. presenting self-antigens)
makes selection of suitable donor organs for transplantation very complex and inefficient

Question 7

how do peptides end up on the surface of cells bound to MHC molecules?

Answer 7

peptides from the protein antigen synthesised in the cytoplasm of a cell (endogenous antigens) are usually presented by class I molecules
Peptides derived from exogenous Ag are generally presented by class II MHC molecules 
in both cases, the protein Ag's to be processed into peptides that are capable of binding MHC molecules

Question 8

How are antigens presented on MHC class I molecules?

Answer 8

Intracellular antigens will go into the proteasome (cleaves the antigen into short peptide fragments)
Short peptide fragments are transported into the ER using a TAP transporter (binds peptides which are ideal to bind to the MHC class I molecules)
Class I molecules are assembled with b2M inside the ER
MHC-1/peptide complex is released from the ER via exocytosis and is found on the cell surface.

Question 9

How are antigens presented on MHC class II molecules?

Answer 9

the antigen is endocytose into intracellular vesicular inside the cell
protein is cleaved to peptides by acid proteases in vesicles
vesicle fuse with vesicles containing MHC class II molecules
peptides bind MHC class II molecules
MHC-II/peptide complex then transported inside vesicles to the cell surface

Question 10

How do class II molecules leave the ER and enter the endocytic pathway?

Answer 10

1. MHC class II molecules bind to invariant chain in the ER - prevents peptides binding in the groove of MHC-II
2. in endocytic pathway, lysosomal enzymes degrade this leaving CLIP peptide associated with the binding groove.
3. peptides from the antigen displace CLIP when they bind
4. HLA-DM, class II molecule, is required for loading of peptides into the groove.

Question 11

what is the role of LMP?

Answer 11

bind to the proteasome and change the proteasome specificity

LMPs are expressed during inflammation