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Terminal Deoxynucleotidyl Transferase Establishes and Broadens Antiviral CD8⁺ T Cell Immunodominance Hierarchies¹

S. M. Mansour Haeryfar^2,*,, Heather D. Hickman^*, Kari R. Irvine^*, David C. Tscharke^*,, Jack R. Bennink^* and Jonathan W. Yewdell^2,*

^* Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada; and School of Biochemistry and Molecular Biology, Australian National University, Canberra, Australian Capital Territory, Australia

The action of TdT on mouse TCR genes accounts for 90% of T cell repertoire diversity. We report that in TdT^–/– mice, total T_CD8⁺ responses to influenza and vaccinia viruses are reduced by 30% relative to wild-type mice. We find that T_CD8⁺ responses to three subdominant influenza virus determinants are reduced to background values in TdT^–/– mice while responses to three immunodominant determinants undergo a major reshuffling. A similar reshuffling occurs in T_CD8⁺ responses to immunodominant vaccinia virus determinants, and is clearly based on broad differences in TCR family usage and CDR3 length between wild-type and TdT^–/– mice. These findings demonstrate that TdT plays a critical role in the magnitude and breadth of anti-viral T_CD8⁺ responses toward individual determinants and suggests that germline TCR repertoire bias toward the most dominant determinants is a major factor in establishing immunodominance hierarchies.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.

² Address correspondence and reprint requests to Dr. Jonathan W. Yewdell, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Room 211, Building 4, 4 Center Drive, Bethesda, MD 20892. E-mail address: jyewdell{at}nih.gov or Dr. S. M. Mansour Haeryfar, Department of Microbiology and Immunology, University of Western Ontario, London, Ontario N6A 5C1, Canada. E-mail address: mansour.haeryfar{at}schulich.uwo.ca

³ Abbreviations used in this paper: T_CD8⁺, targets for CD8⁺ T lymphocyte; WT, wild type; IAV, influenza A virus; ICS, intracellular cytokine staining; PEC, peritoneal exudate cell; LCMV, lymphocytic choriomeningitis virus; BMDC, bone marrow-derived dendritic cell; rVV, recombinant vaccinia virus; HK, Hong Kong strain; VV, vaccinia virus.

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