MHC Ag presentation & T cell recognition (1/4) Flashcards
How do T cells recognize antigens?
T cell receptors (TCR) recognize both the peptide (antigen) and the MHC molecule which presents the antigen
How is the diversity of TCRs generated?
Somatic recombination (creates 10^13 different TCRs) + a selection mechanism
How is the diversity of MHC created? (2 main ways)
- Having multiple alleles that encode MHC that vary from individual to individual
- Have multiple loci: different MHC structures in an individual (MHC I and II)
How does the adaptive immune system develop T cell clones that can both recognize the individual’s MHC molecules & pathogen peptides prior to encountering the pathogen?
Use self-peptides as a surrogate for pathogen peptides & select on self-MHC molecules.
Complication: the TCR of randomly generated T cell colones could strongly recognize self-peptides presented in self-MHC & mount a self-attack (which is why we have clonal selection)
What is thymic education?
What are the 2 steps?
T cell selection process that has 2 steps
First step: postive selection for T cell clones that recognize self-peptide in an individual’s own MHC molecules
Second step: negative selection that deletes overtly self reactive clones with high affinity for self peptide
What is immunologic self?
unique set of self-peptide/MHC molecules = individual’s unique T cell repertoir
What is the basis of skin graft rejection?
Immunologic self/MHC alleles
Called histocompatibility/histoincompatibility
What is MHC I?
Targets intracellular bacteria & viruses
Tells T cell that infected cell should be killed
Uses CD8
On virtually all nucleated cells
Beta2micro is part of the cytoplasmic domain & is used clinically to measure level of immune response
Only 1/2 of the domain is diversifiable – alpha chain with alpha 1, 2, and 3 domains. Note that it is a folded chain.
The beta chain is small & not MHC encoded
What is MHC II?
Target extracellular bacteria (macrophage/DC present) or extracellular pathogen/toxin (B cell presents)
Tells T cell to provide help to the infected cell to eliminate the pathogen
Uses CD4
More diversification is possible bc in the dimer, both domains (alpha and beta chain) are diversifiable & are encoded within the MHC
How do peptides bind the MHC?
Cluster of tyrosines recognize NH3+ on the peptide. NH2 terminus is to the left for both classes
For MHC I, 9-AA long peptides bind mainly w/interaction between 2nd and 9th residue. Class I= very precise
MHC II will bind proteins of different lengths, peptide ends are free. Always tethered in the middle. These are more involved in autoimmunity
How is diversity in MHC genes generated? (2 mechanisms)
Duplication of a gene locus in an individual –> multiple loci (polygenism)
Development of multiple alleles at a locus among individuals in the species (polyallelism)
What genetic features confer advantage in creating MHC?
The individual with the rarest allele has the best chance of survivial because the pathogen is less likely to have seen it
If you have more MHC structures, you also have an advantage (up to a point- too many & you get too large of an immune self –> save fewer good MHC’s during negative selection
