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Multiple Glycines in TCR -Chains Determine Clonally Diverse Nature of Human T Cell Memory to Influenza A Virus¹

Yuri N. Naumov^2,*, Elena N. Naumova, Maryam B. Yassai, Kalyani Kota^*, Raymond M. Welsh^* and Liisa K. Selin^*

^* Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655; Blood Research Institute, The Blood Center of Wisconsin, Milwaukee, WI 53201; and Department of Public Health and Family Medicine, Tufts University School of Medicine, Boston, MA 02111

Detailed assessment of how the structural properties of T cell receptors affect clonal repertoires of Ag-specific cells is a prerequisite for a better understanding of human antiviral immunity. Herein we examine the TCR repertoires of CD8 T cells reactive against the influenza A viral epitope M1_58–66, restricted by HLA-A2.1. Using molecular cloning, we systematically studied the impact of -chain usage in the formation of T cell memory and revealed that M1_58–66-specific, clonally diverse VB19 T cells express -chains encoded by multiple AV genes with different CDR3 sizes. A unique feature of these TCRs was the presence of CDR3 fitting to an AGA(G_n)GG-like amino acid motif. This pattern was consistent over time and among different individuals. Further molecular assessment of human CD4⁺CD8^– and CD4^–CD8⁺ thymocytes led to the conclusion that the poly-Gly/Ala runs in CDR3 were a property of immune, but not naive, repertoires and could be attributed to influenza exposure. Repertoires of T cell memory are discussed in the context of clonal diversity, where poly-Gly/Ala runs in the CDR3 of - and β-chains might provide high levels of TCR flexibility during Ag recognition while gene-encoded CDR1 and CDR2 contribute to the fine specificity of the TCR-peptide MHC interaction.

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 U19-AI057319 (to Y.N.N.), U19-AI062627 (to Y.N.N. and E.N.N.) and AI45751 (to L.K.S.). The contents of this publication are solely the responsibility of the authors and do not represent the official view of the National Institutes of Health.

² Address correspondence and reprint requests to Dr. Yuri N. Naumov, Department of Pathology, University of Massachusetts Medical School, 55 Lake Avenue, Worcester, MA 01655. E-mail address: Yuri.Naumov{at}umassmed.edu

³ Abbreviations used in this paper: pMHC, immunogenic peptides loaded into class I MHC molecules; 4SP, CD4⁺CD8^–; 8SP, CD4^–CD8⁺.

⁴ The online version of this article contains supplemental material.