T cell and B cell activation, MHC lecture II Flashcards
MHC polygeny and polymorphism?
There are several class I and II genetic loci each expressing a different protein.
Most loci are highly polymorphic in the population – your MHC molecules are different to mine.
This has been driven by natural selection driven by pathogens.
Today, this creates some problems in clinical situations.
Most proteins are similar in all of us, but not MHC.
Driven by infections that humans have been exposed to over many years.
Causes problems in eg. transplantation, skin grafts etc.
MHC is the reason we need to match donor and recipient.
Vaccines- will they work the same in everyone, if all MHC is different?
How many polymorphic MHC proteins do we express?
Several highly polymorphic MHC proteins.
Human MHCI isotypes- HLA-A,B,C,D,E,F,G (HLA-E, F & G do not present peptides to CD8 T cells).
Human MHCII isotypes- HLA-DM, DO, DP, DQ, DR (HLA-DM and DO regulate peptide loading but do not present peptides).
DR is most important.
Lot of variants in population
DM kicks out fragment of invariant chain.
E, F, G engage NK cells
How many polymorphic genes are found in MHCI and II?
MHCI- 3 highly polymorphic genes.
MHCII 1 highly polymorphic and 2 polymorphic genes.
MHCII alpha chain (DRA) is virtually invariant.
How are genes/alleles arranged in MHC?
The combination of HLA alleles on chromosome 6 in an individual is called a haplotype.
Typically an individual would have at least 6 different antigen presenting MHC per chromosome:
- 3 class I genes, HLA-A, HLA-B & HLA-C.
- 3 (sometimes 4) class II genes, HLA-DR, HLA-DP, HLA-DQ.
- so with 2 haplotypes per individual, in total, there are 6 class I and at least 6 class II MHC molecules.
Meiotic recombination occurs at ~2% frequency.
Over evolutionary time a few hundred alleles have recombined to generate many thousands of haplotypes.
2 MHC haplotypes per individual means millions of different combinations in the population.
Added to ‘polygeny’ is MHC polymorphism.
Where is MHC polymorphism focused?
Peptide binding site.
Some of the positions have many different variants.
Due to differences, the peptides that peoples’ MHC can bind will be different.
Variant positions are involved in binding peptide or in interactions with the T cell receptor
What are MHC peptide binding motifs and what do they contain?
Motifs contain anchor proteins.
2/3 ‘anchor’ positions restrict the multiplicity of peptides that can be bound.
For class I MHC, peptide positions 2 and 9 are usually restricted to 1 or 2 amino acids.
Since class II peptides are variable in length, identifying anchor positions is more difficult.
Bind a lot of different peptides.
Anchor residues- these positions need to be satisfied for binding.
More difficult for class 2- due to open ends. Length is variable, so harder to line up (more difficult to spot motifs).
What to anchor proteins correspond to?
Anchor positions correspond to peptide side chains that fit into MHC pockets.
What is MHC restriction?
What is self tolerance?
Restriction- Our T cells ‘learn’ to recognise antigen (peptides) in the context of our personal set of MHC molecules.
Basis of self tolerance- T cells that recognise MHC + a self peptide need to be eliminated.
T cell repertoire selected to recognise peptides in the context of each individual’s MHC.
We are tolerant to own antigens- autoimmunity happens when this goes wrong.
How are T cells positively and negatively selected?
Selection for self MHC reactive T cells:
Positive selection of a:B T cells by cortical epithelial cells in the thymus-
T cell binds to epithelial cell MHC- if weak or no binding occurs, cell dies. If moderate or strong binding, cell lives.
T cell receptor repertoire is variable.
Want to select T cells that bind our MHC- positive selection.
Elimination of self-peptide reactive T cells:
Negative selection of a:B T cells by dendritic cells, macrophages and other cells in the thymus.
T cell binds to dendritic cell MHC- if tight binding, cell dies. If moderate binding, cell lives.
What is needed for T cells to bind/recognise MHC peptide composite surface?
Needs to fit properly, so needs a complementary shape.
Why is it advantageous to be heterozygous in peptide selection?
Advantageous to be heterozygous, and for them to not be similar- broader coverage.
The total set of peptides from a given pathogen that can be presented by
MHC molecules.
The sub-set of peptides from a given pathogen that can be presented by
this individual’s set of MHC molecules
(their haplotype).
Heterozygotes (2 different haplotypes)
can present a broader range of peptides.
How does MHC heterozygosity affect HIV infected individuals?
MHC heterozyosity improves outcome in HIV infected individuals.
Better outcome (slower progression) also correlates with particular MHC class I alleles (e.g HLA-B27) presumably because they are best at binding and presenting HIV peptides.
Present greater no. peptides from HIV virus.
Activate more CD8 cells.
Wat are some pros and cons of MHC polymorphism?
Pros:
Good for survival of the species.
More diverse peptides presented.
Harder for pathogen to evade the immune response.
Harder to evade cause of presence of more T cells.
Cons:
Obstructs transplantation
and tissue grafts.
Complicates vaccine design- needs to work effectively with most peoples’ MHC.
How do superantigens work?
Superantigens link MHC molecules and T cell receptors in a distinct way.
Superantigens are produced by bacteria, viruses and mycoplasmas
-e.g cause toxin shock syndrome.
They are not processed and bind to the outside of MHC molecules.
Bind mainly to Vbeta of TCR.
Each superantigen is specific for one or a few of the 20-50 Vb genes.
A superantigen can stimulate 2-20% of all T cells.
Massive cytokine production leading to serious illness and even death.
Don’t bind to groove.
Bind to B half of T cell receptor.
Huge no. T cells activated, cytokines made- this is TSS.
Usually cytokine production that makes you feel ill, not pathogen.
How do superantigens bind to TCR/MHC?
Cross linking of antigen presenting cell and T cell.
