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Analysis of TCR Combinations used by Simian Immunodeficiency Virus-Specific CD8⁺ T Cells in Rhesus Monkeys: Implications for CTL Immunodominance¹

Atsuhiko Hasegawa^*, Chikaya Moriya^2,, Huining Liu^*, William A. Charini, Heather C. Vinet^*, Ramu A. Subbramanian^3,, Pritha Sen, Norman L. Letvin and Marcelo J. Kuroda^4,*

^* Division of Immunology, Tulane National Primate Research Center, Tulane University Health Sciences Center, Covington, LA 70433; and Division of Viral Pathogenesis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215

Immunodominance is a common feature of Ag-specific CTL responses to infection or vaccines. Understanding the basis of immunodominance is crucial to understanding cellular immunity and viral evasion mechanisms and will provide a rational approach for improving HIV vaccine design. This study was performed comparing CTLs specific for the SIV Gag p11C (dominant) and SIV Pol p68A (subdominant) epitopes that are consistently generated in Mamu-A*01⁺ rhesus monkeys exposed to SIV proteins. Additionally, vaccinated monkeys were used to prevent any issues of antigenic variation or dynamic changes in CTL responses by continuous Ag exposure. Analysis of the TCR repertoire revealed the usage of higher numbers of TCR clones by the dominant p11C-specific CTL population. Preferential usage of specific TCRs and the in vitro functional TCR-- and --chain-pairing assay suggests that every peptide/MHC complex may only be recognized by a limited number of unique combinations of - and -chain pairs. The wider array of TCR clones used by the dominant p11C-specific CTL population might be explained by the higher probability of generating those specific TCR chain pairs. Our data suggest that Ag-specific naive T cell precursor frequency may be predetermined and that this process dictates immunodominance of SIV-specific CD8⁺ T cell responses. These findings will aid in understanding immunodominance and designing new approaches to modulate CTL responses.

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 National Institutes of Health Grants AI048400 and AI058882 (to M.J.K.) and AI020729 (to N.L.L.), the Harvard Center for AIDS Research Grant AI060354, and the base grants to the Tulane National Primate Research Center (RR000164) and New England Primate Research Center (RR000168).

² Current address: International Research Center for Infectious Diseases, Institute of Medical Sciences, University of Tokyo, Tokyo 108-8639, Japan.

³ Current address: Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229.

⁴ Address correspondence to Dr. Marcelo J. Kuroda, Division of Immunology, Tulane National Primate Research Center, Tulane University Health Sciences Center, 18703 Three Rivers Road, Covington, LA 70433. E-mail address: mkuroda{at}tulane.edu

⁵ Abbreviations used in this paper: MFI, mean fluorescence intensity.

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