Terminal Deoxynucleotidyltransferase Is Required for the Establishment of Private Virus-Specific CD8+ TCR Repertoires and Facilitates Optimal CTL Responses

Abstract

Virus-immune CD8+ TCR repertoires specific for particular peptide-MHC class I complexes may be substantially shared between (public), or unique to, individuals (private). Because public TCRs can show reduced TdT-mediated N-region additions, we analyzed how TdT shapes the heavily public (to DbNP366) and essentially private (to DbPA224) CTL repertoires generated following influenza A virus infection of C57BL/6 (B6, H2b) mice. The DbNP366-specific CTL response was virtually clonal in TdT−/− B6 animals, with one of the three public clonotypes prominent in the wild-type (wt) response consistently dominating the TdT−/− set. Furthermore, this massive narrowing of TCR selection for DbNP366 reduced the magnitude of DbNP366-specific CTL response in the virus-infected lung. Conversely, the DbPA224-specific responses remained comparable in both magnitude and TCR diversity within individual TdT−/− and wt mice. However, the extent of TCR diversity across the total population was significantly reduced, with the consequence that the normally private wt DbPA224-specific repertoire was now substantially public across the TdT−/− mouse population. The key finding is thus that the role of TdT in ensuring enhanced diversity and the selection of private TCR repertoires promotes optimal CD8+ T cell immunity, both within individuals and across the species as a whole.