10 - MHC - Partridge Flashcards
What does MHC stand for?
major histocompatibility complex
Where are the MHC genes located and how was the complex first discovered?
located on chromosome 6. first discovered in graft rejection research
What is MHC also known as in humans?
HLA - human leucocyte antigen (eg HLA-A/B/C)
Give one feature of MHC molecules that enables it to do its ob in recognising antigen
very polymorphic. eg > 1400 alleles of HLA-B locus. with each allele containing around 20 different aa substitutions
What is the overall role of the MHC complex?
major role in antigen presentation and stimulating T cell responses
T lymphocytes can only recognise ____ in the context of ___-___ molecules
antigen
self-MHC
Describe an experiment that identified the use of an MHC molecule. What 2 proposals were then suggested from this? (draw a diagram)
- 2 mice infected with virus
- virally infected cells from mouse A isolated
- T cells from both mice A/B obtained and shown that T cells from mouse A could respond and kill the virally infected cell
- 2 proposals; 1) 2 receptors on T cells. one for MHC and one for antigen. 2) one TCR which recognised both antigen and MHC
311 - 10 word
Why is it that there is a lower chance of graft rejection if receive transplant off a family member?
inherit MHC alleles from family therefore lower chance of rejection because have the same MHC
How was the MHC-TCR complex finally observed?
X ray crystallography
Describe the 2 causes of MHC proteins (including their gene loci, what cells express them, what peptides they process)
MHC class I (HLA-A/B/C);
- expressed by all nucleated cells (not RBCs, hence why blood transfusions aren’t as complex)
- present peptides derived from endogenous proteins as a result of cell viral/intracellular bacteria infection
- present to CTT (CD8+ve)
MHC Class II (HLA-DP/DQ/DR)
- expressed by B cells, dendritic cells, macrophages
- present peptides derived from exogenous proteins (eg macrophages taking up bacteria) to helper T cells (CD4+ve)
Draw the MHC-1 protein structure
311 - 10 word
Draw the MHC-II protein structure
311 - 10 word
Talking about MHCI/II protein structure…
what are the membrane proximal / distal domains like?
proximal; Ig like
distal; contain polymorphisms that bind peptide
DESCRIBE (overall) the structure of the MHCI/II molecules
MHCI - polymorphic TM a chain, invariant B2-microglobulin domain
MHCII - polymorphic TM a and B chains
What are the similarities between MHC-I/II structures and how they bind the peptides
- both peptide binding grooves contain a B sheet
- polymorphic residues form specificity pockets on the MHC which bind certain anchor residues along the peptide which hold it in place
Describe the peptides MHC I binds and how they bind int
- MHCI binds peptides around 8-10aa long. crystal structure = > closed than MHC II
- the N/C terminus of the peptide binds invariant residues at the ends of the grooves
- 2/3 anchor residues bind to the specificity pockets formed by polymorphic residues
Describe the peptides MHC II binds and how they bind int
- peptides are slightly longer - 13-25aa
- crystal structure = > open groove therefore binding to bigger structures
- anchor residues bind specificity pockets…
What were the 2 results that crystallographic studies showed?
1) MHC binds antigen
2) TCR binds antigen associated with self-MHC
Draw a diagram showing the TCR binding to the MHC-I molecule
311 -10 word
What are the functions of the CDR1/2/3 regions of V region in the TCR?
CDR1/2 binds self MHC (germline encoded)
CDR3 binds peptide (variation introduced by junctional diversity)
Describe the specificity of MHC molecules
degenerate specificity. recognise a wide variety of peptides, unlike TCRs
When are MHC molecules expressed on the surface of antigen presenting cells and when do the bound peptides dissociate from MHC?
- expressed on surface when they become associated with the peptide. peptide is an integral part of MHC strucutre
- bound peptides dissociate v slowly from MHC. allows interaction with TCR that has the correct receptor
What are the circumstances for RECOGNITION/NO RECOGNITION when a TCR binds to antigen + MHC?
RECOGNITION;
- T cell w/ correct receptor binds to both peptide and self-MHC
NO RECOGNITION;
- T cell does not have correct receptor for antigen but can recognise self MHC
- T cell cannot recognise self MHC (wrong class)
Describe the whole process of antigen presentation by MHCI
- eg virally infected host cell presenting to CD8+ve cytotoxic T cell
- intracellular antigen taken up by proteasome (IFN exposure can modify the proteasome -> immunoproteasome which better cleaves the proteins to peptides 8-10aa long)
- peptides of correct length released -> cytosol
- moved to ER by ATP-hydrolysis dependent TAP protein (transporter associated w/ antigen presentation)
- peptide loaded onto MHCI molecules(requires chaperones) and expressed on cell surface
