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Contribution of TCR-β Locus and HLA to the Shape of the Mature Human Vβ Repertoire¹

J. Joseph Melenhorst^2,*, Matthew D. H. Lay^¶, David A. Price^,||, Sharon D. Adams, Josette Zeilah^*, Edgardo Sosa^*, Nancy F. Hensel^*, Dean Follmann, Daniel C. Douek, Miles P. Davenport^¶ and A. John Barrett^*

^* Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892; Human Immunology Section, Vaccine Research Center, Department of Transfusion Medicine Clinical Center, and Biostatistics Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; ^¶ Centre for Vascular Research, University of New South Wales, Kensington, Australia; and ^|| Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff, United Kingdom

T cells that survive thymic selection express a diverse array of unique heterodimeric β TCRs that mediate peptide-MHC Ag recognition. The proportion of the total T cell repertoire that expresses a particular Vβ protein may be determined by a variety of factors: 1) germline preference for use of particular Vβ genes; 2) allelic effects on the expression of different Vβ genes; and 3) HLA effects on the expression of different Vβ genes (acting via thymic selection and/or peripheral mechanisms). In this study, we show that Vβ usage by human CD4⁺ and CD8⁺ T cells in neonatal and adult donors is highly correlated between unrelated individuals, suggesting that a large proportion of the observed pattern of Vβ expression is determined by factors intrinsic to the TCR-β locus. The presence of identical TCR alleles (within an individual) leads to a significantly better correlation between CD4⁺ and CD8⁺ T cells with respect to Vβ expression; these effects are, however, relatively minor. The sharing of HLA alleles between individuals also leads to an increased correlation between their Vβ expression patterns, although this did not reach statistical significance. We therefore conclude that the correlation in Vβ expression patterns between CD4⁺ and CD8⁺ T cells can be explained predominantly by germline TCR-β locus factors and not TCR-β allelic or HLA effects.

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¹ D.A.P. is a Medical Research Council (U.K.) Senior Clinical Fellow. M.P.D. is a Sylvia and Charles Viertel Charitable Foundation Senior Medical Research Fellow. This work was supported in part by the James S. McDonnell Foundation 21st Century Research Award/Studying Complex Systems, the Australian Research Council, the National Health and Medical Research Council, and the Intramural Research Programs of the National Heart, Lung, and Blood Institute and the National Institute of Allergy and Infectious Diseases, U.S. National Institutes of Health.

² Address correspondence and reprint requests to Dr. J. Joseph Melenhorst, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10-CRC, Room 3-5320, 10 Center Drive, Bethesda, MD 20892-1202. E-mail address: melenhoj{at}nhlbi.nih.gov

³ Abbreviations used in this paper: SNP, single nucleotide polymorphism; UCB, umbilical cord blood; RSS, recombination signal sequence.