Fixed expression of single influenza virus-specific TCR chains demonstrates the capacity for TCR α- and β-chain diversity in the face of peptide-MHC class I specificity

The characteristics of the TCR repertoire expressed by epitope-specific CD8⁺ T cells can be an important determinant of the quality of immune protection against virus infection. Most studies of epitope-specific TCR repertoires focus solely on an analysis of TCR β-chains, rather than the combined TCRαβ heterodimers that confer specificity. Hence, the importance of complementary α- and β-chain pairing in determining TCR specificity and T cell function is not well understood. Our earlier study of influenzaspecific TCR repertoires in a C57BL/6J mouse model described a structural basis for preferred TCRαβ pairing that determined exquisite specificity for the D^bPA₂₂₄ epitope from influenza A virus. We have now extended this analysis using retrogenic mice engineered to express single TCR α-or β-chains specific for the D^bNP₃₆₆ or D^bPA₂₂₄ epitopes derived from influenza A virus. We found that particular TCRαβ combinations were selected for recognition of these epitopes following infection, indicating that pairing of certain α- and β-chain sequences is key for determining TCR specificity. Furthermore, we demonstrated that some TCRab heterodimers were preferentially expanded from the naive repertoire in response to virus infection, suggesting that appropriate ab pairing confers optimal T cell responsiveness to Ag.