Reversed T Cell Receptor Docking on a Major Histocompatibility Class I Complex Limits Involvement in the Immune...

The anti-viral T cell response is drawn from the naive T cell repertoire. During influenza infection, the CD8⁺ T cell response to an H-2D^b-restricted nucleoprotein epitope (NP₃₆₆) is characterized by preferential expansion of T cells bearing TRBV13⁺ T cell receptors (TCRs) and avoidance of TRBV17⁺ T cells, despite the latter dominating the naive precursor repertoire. We found two TRBV17⁺ TCRs that bound H-2D^b-NP₃₆₆ with a 180° reversed polarity compared to the canonical TCR-pMHC-I docking. The TRBV17 β-chain dominated the interaction and, whereas the complementarity determining region-3 (CDR3) loops exclusively mediated contacts with the MHC-I, peptide specificity was attributable to germline-encoded recognition. Nevertheless, the TRBV17⁺ TCR exhibited moderate affinity toward H-2D^b-NP₃₆₆ and was capable of signal transduction. Thus, the naive CD8⁺ T cell pool can comprise TCRs adopting reversed pMHC-I docking modes that limit their involvement in the immune response.