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Homogenization of TCR Repertoires within Secondary CD62L^high and CD62L^low Virus-Specific CD8⁺ T Cell Populations¹

Katherine Kedzierska^2,*, Vanessa Venturi, Sophie A. Valkenburg^*, Miles P. Davenport, Stephen J. Turner^* and Peter C. Doherty^*,

^* Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria; Department of Haematology, Prince of Wales Hospital and Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia; and Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105

Influenza virus-specific CD8⁺ T cell clonotypes generated and maintained in C57BL/6J mice after respiratory challenge were found previously to distribute unequally between the CD62L^low "effector" (T_EM) and CD62L^high "central" (T_CM) memory subsets. Defined by the CDR3β sequence, most of the prominent TCRs were represented in both the CD62L^high and CD62L^low subsets, but there was also a substantial number of diverse, but generally small, CD62L^high-only clonotypes. The question asked here is how secondary challenge influences both the diversity and the continuity of TCR representation in the T_CM and T_EM subsets generated following primary exposure. The experiments use single-cell RT-PCR to correlate clonotypic composition with CD62L phenotype for secondary influenza-specific CD8⁺ T cell responses directed at the prominent D^bNP₃₆₆ and D^bPA₂₂₄ epitopes. In both the acute and long-term memory phases of the recall responses to these epitopes, we found evidence of a convergence of TCR repertoire expression for the CD62L^low and CD62L^high populations. In fact, unlike the primary response, there were no significant differences in clonotypic diversity between the CD62L^low and CD62L^high subsets. This "TCR homogenization" for the CD62L^high and CD62L^low CD8⁺ populations recalled after secondary challenge indicates common origin, most likely from the high prevalence populations in the CD62L^high central memory set. Our study thus provides key insights into the TCR diversity spectrum for CD62L^high and CD62L^low T cells generated from a normal, unmanipulated T cell repertoire following secondary challenge. A better understanding of TCR selection and maintenance has implications for improved vaccine and immunotherapy protocols.

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 an Australian National Health and Medical Research Council Burnet Fellowship and the National Institutes of Health Grant AI70251 awarded to P.C.D. and a National Health and Medical Research Council Project Grant 454312 awarded to K.K. S.J.T. is a Pfizer Senior Research Fellow, M.P.D. is a Sylvia and Charles Viertel Senior Medical Research Fellow, and K.K. is a National Health and Medical Research Council R. D. Wright Research Fellow.

² Address correspondence and reprint requests to Dr. Katherine Kedzierska, University of Melbourne, Royal Parade, Parkville, Victoria 3010, Australia. E-mail address: kkedz{at}unimelb.edu.au

³ Abbreviations used in this paper: T_CM, central memory T cell; T_EM, effector memory T cell; H, viral hemagglutinin molecule; N, viral neuraminidase; i.n., intranasally; PR8, A/PR/8/34 H1N1 influenza virus; HKx31, A/HKx31 H3N2 influenza virus.