Terminal deoxynucleotidyltransferase is required for the establishment of private virus-specific CD8+ TCR repertoires and facilitates optimal CTL responses

J Immunol. 2008 Aug 15;181(4):2556-62. doi: 10.4049/jimmunol.181.4.2556.

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 D(b)NP(366)) and essentially private (to D(b)PA(224)) CTL repertoires generated following influenza A virus infection of C57BL/6 (B6, H2(b)) mice. The D(b)NP(366)-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(b)NP(366) reduced the magnitude of D(b)NP(366)-specific CTL response in the virus-infected lung. Conversely, the D(b)PA(224)-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(b)PA(224)-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / enzymology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / virology
  • Clone Cells
  • Cytotoxicity, Immunologic* / genetics
  • DNA Nucleotidylexotransferase / deficiency
  • DNA Nucleotidylexotransferase / genetics
  • DNA Nucleotidylexotransferase / physiology*
  • Epitopes, T-Lymphocyte / biosynthesis
  • Epitopes, T-Lymphocyte / immunology*
  • Female
  • Gene Rearrangement, beta-Chain T-Cell Antigen Receptor*
  • Influenza A Virus, H3N2 Subtype / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Orthomyxoviridae Infections / enzymology
  • Orthomyxoviridae Infections / immunology
  • Orthomyxoviridae Infections / metabolism
  • Receptors, Antigen, T-Cell, alpha-beta / biosynthesis*
  • Receptors, Antigen, T-Cell, alpha-beta / genetics
  • T-Lymphocytes, Cytotoxic / enzymology
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Cytotoxic / virology

Substances

  • Epitopes, T-Lymphocyte
  • Receptors, Antigen, T-Cell, alpha-beta
  • DNA Nucleotidylexotransferase