Fixed expression of single influenza virus-specific TCR chains demonstrates the capacity for TCR α- and ß-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 ß-chains, rather than the combined TCRαß heterodimers that confer specificity. Hence, the importance of complementary α- and ß-chain pairing in determining TCR specificity and T cell function is not well understood. Our earlier study of influenza-specific TCR repertoires in a C57BL/6J mouse model described a structural basis for preferred TCRαß pairing that determined exquisite specificity for the D(b)PA224 epitope from influenza A virus. We have now extended this analysis using retrogenic mice engineered to express single TCR α- or ß-chains specific for the D(b)NP366 or D(b)PA224 epitopes derived from influenza A virus. We found that particular TCRαß combinations were selected for recognition of these epitopes following infection, indicating that pairing of certain α- and ß-chain sequences is key for determining TCR specificity. Furthermore, we demonstrated that some TCRαß heterodimers were preferentially expanded from the naive repertoire in response to virus infection, suggesting that appropriate αß pairing confers optimal T cell responsiveness to Ag.