Degenerate recognition of T cell epitopes: impact of T cell receptor reserve and stability of peptide:MHC complexes

The concept of molecular mimicry suggests that microbial pathogens might activate antigen-specific T cells that then cross-react with endogenous antigens and result in the generation of autoimmunity. Here we discuss several under-represented factors impacting the ability of TCRs to recognize a wide spectrum of related peptide:MHC (pMHC) ligands. Two of these factors include the affinity of the peptide for MHC and the level of TCR expression. Thymocytes that recognize peptides with low affinity for MHC avoid negative selection, but mature T cells, by virtue of increased TCR expression, will proliferate in response to these same unstable pMHC complexes. While the expression of a reserve of antigen receptors expands the potential number of epitopes for which a T cell can cross-react, phosphatase activity provides a tuning mechanism to increase the threshold level of activation. Thus, degenerate recognition of T cell epitopes involves the stability of the peptide:MHC complex, the number of TCR expressed, and the level of phosphatase activity.