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Terminal Deoxynucleotidyltransferase Is Required for the Establishment of Private Virus-Specific CD8⁺ TCR Repertoires and Facilitates Optimal CTL Responses¹

Katherine Kedzierska^2,*, Paul G. Thomas^2,, Vanessa Venturi, Miles P. Davenport, Peter C. Doherty^*,, Stephen J. Turner^* and Nicole L. La Gruta^3,*

^* Department of Microbiology and Immunology, University of Melbourne, Parkville, Australia; Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105; and Complex Systems in Biology Group, Centre for Vascular Research, University of New South Wales, Kensington, Australia

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 D^bNP₃₆₆) and essentially private (to D^bPA₂₂₄) CTL repertoires generated following influenza A virus infection of C57BL/6 (B6, H2^b) mice. The D^bNP₃₆₆-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 D^bNP₃₆₆ reduced the magnitude of D^bNP₃₆₆-specific CTL response in the virus-infected lung. Conversely, the D^bPA₂₂₄-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 D^bPA₂₂₄-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.

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¹ This work was supported by Australian National Health and Medical Research Council Project Grants AI454595 (to P.C.D.), AI454312 (to K.K.), and AI350395 (to N.L.L.); a National Health and Medical Research Council Burnet Award; Science Technology Innovation funds from the Government of Victoria, Australia (AI29579); Australian Research Council Discovery Grant DP0771340 (to M.P.D., S.J.T., and V.V.); and National Institutes of Health Grants AI70251 (to P.C.D.) and AI065097 (to P.G.T.). K.K. is the recipient of a University of Melbourne Early Career Researcher grant. K.K. and N.L.L. are National Health and Medical Research Council R. Douglas Wright Fellows; M.P.D. is a Sylvia and Charles Viertel Senior Medical Research Fellow; and S.J.T. is a Pfizer Australia Research Fellow.

² K.K. and P.G.T. contributed equally.

³ Address correspondence and reprint requests to Dr. Nicole L. La Gruta, Department of Microbiology and Immunology, University of Melbourne, Parkville VIC 3010. E-mail address: nllg{at}unimelb.edu.au

⁴ Abbreviations used in this paper: pMHC, peptide plus MHC; BAL, bronchoalveolar lavage; EID₅₀, egg infectious dose; i.n., intranasal; HKx31, A/Hong Kongx31 virus; NP, nucleoprotein; PA, acid polymerase; PR8, A/Puerto Rico/8/34 influenza A virus; wt, wild type.