Full extent of typical T-cell receptor degeneracy

Determine the full extent of degeneracy of typical T-cell receptors in peptide recognition by quantifying the number and diversity of distinct peptides presented by MHC class I molecules that a typical T-cell receptor can recognize across different peptide–MHC contexts.

Background

T-cell receptors (TCRs) can exhibit substantial cross-reactivity, with some autoimmune T cells experimentally shown to recognize over one million distinct peptides. However, for typical TCRs, comprehensive measurements of the breadth of peptide recognition are limited by current high-throughput experimental capabilities, leaving the true scope of degeneracy uncertain.

In this paper, the authors estimate peptide recognition diversity using structure-based position weight matrices and entropy as proxies, finding a median of about 10 bits (~10^3 peptides) for human and mouse TCR–MHC class I pairs, compared to much higher degeneracy for MHC presentation alone. They note that these estimates are likely lower bounds due to constraints of structural templates and limited reliability of relaxed designs beyond approximately five substitutions, motivating the need to more fully resolve the true extent of typical TCR degeneracy.