Lecture 10: MHC Genetics, Structure and Peptide Selection Flashcards
What makes it difficult for MHC to detect pathogenic peptide ligands?
the number of potential MHC peptide ligands that can be generated by degradation of self and non-self proteins is vast
How is MHC able to detect pathogenic peptide ligands?
these molecules are able to bind a large number of different peptides, in the hope that some of those peptides will belong to the pathogen
How are MHC molecules able to bind many different peptides?
each MHC molecule has a single binding groove which can bind to many different peptide fragments of different lengths of amino acids
What are the two “faces” of antigenic peptides?
one is exposed to the TCR and the other is buried in the MHC binding groove
What are anchor residues?
“pockets” in the peptide binding site of MHC molecules that can only accommodate certain residues, but the interaction between the pocket and those residues is very strong
What is the role of the residues pointing outside of the MHC (variable residues)?
since they contribute little to binding, these residues can vary without compromising the strength of the MHC-peptide interaction
How many different peptides can the binding groove of an MHC molecule accommodate?
thousands of different peptides sharing the same “anchor” residues
An MHC molecule can present a ___ number of different peptides, but these still represent a ___ fraction of the whole ___.
large
small
peptidome
How is MHC able to expand the number of different peptides that cells are able to present?
MHC genes are polymorphic i.e. polymorphism varies the structure of the peptide binding site and each allele binds a different set of proteins
What are the implications of polymorphism?
we are diploid and we can express different MHC allelic variants in each locus -> this means that since there are three loci encoding MHC I and three loci encoding MHC II, each individual can have up to six genes encoding for MHC I and six encoding for MHC II
What does it mean if each individual can have up to six genes encoding for MHC I and six encoding for MHC II?
each individual can express up to six different MHC class I molecules and six different MHC class II molecules
What is the nature of the genes that encode MHC molecules?
they are clustered
What are HLA and H-2 complexes?
individual names for MHCs in humans and mice respectively
How many allelic variants are there in each locus?
varies but it is very large
What does polygeny and polymorphism allow?
allows each MHC molecule to present a larger fraction of the peptidome
How are MHC molecules able to present the entire self and pathogen “peptidome”?
each individual can present a different (but overlapping) set of peptides -> one MHC molecule may not be able to present a pathogen, however a different MHC molecule will be able to
What does the TCR interact with?
residues from both the antigenic peptide and the MHC molecule
How many TCRs can recognise the MHC-peptide complexes that can be potentially presented by an individual’s MHC?
only a fraction
Which T cells are selected in the thymus and go into circulation?
only those that can recognise your MHC
What do all the selected T cells express?
TCRs which can interact ”a bit” with the peptide-binding site of at least one of your MHC molecules, but not so strongly enough to cause “recognition”
What do normal T cells “ignore”?
the self-peptides but some of them will interact with both the MHC and the peptide strongly enough to “recognise” the complex if the peptide is foreign (new)
What do T cells of each individual recognise?
only the antigenic determinants presented by the MHC allotypes of that individual
