Cross-reactive responses to modified M1₅₈-₆₆ peptides by CD8⁺ T cells that use noncanonical BV genes can describe unknown repertoires

Memory T-cell repertoires are populated by clonotypes selected by an individual's history of antigen exposures. Our previous analysis of middle-age CD8(+) T-cell memory repertoires to the influenza-derived epitope M1(58-66) , described a network of highly cross-reactive BV19 clonotypes responding to M1(58-66) and at least one peptide with a conservative amino acid substitution at either of two TCR contact positions. Here, we report that some substitutions abrogate BV19 responses and favor responses with different BV. Cross-reactive T cells using seven other BV families responded to 12 of 13 Peptides tested. BV12 clonotypes define the most extensive cross-reactive network that encompasses seven Peptides. We generated 3D networks based on the Peptides recognized and BV family used and observed a cluster of five Peptides that includes M1(58-66) and another cluster of five Peptides that does not include M1(58-66) . The first cluster represents Peptides structurally similar to M1(58-66) , and the second represents Peptides with more considerable changes in epitope recognition surface. We hypothesize that the second cluster represents the cross-reactive network around another unknown epitope or epitopes. This data supports a model of stable CD8(+) T-cell memory networks that include a substantial contribution from cross-reactive T cells.