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Rapid and Selective Expansion of Nonclonotypic T Cells in Regulatory T Cell-Deficient, Foreign Antigen-Specific TCR-Transgenic Scurfy Mice: Antigen-Dependent Expansion and TCR Analysis¹

Rahul Sharma^*, Angela Chiao-Ying Ju^*, John T. Kung, Shu Man Fu^2,* and Shyr-Te Ju^2,3,*

^* Department of Medicine, Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, VA 22908; and Institute of Molecular Biology, Academia Sinica, Taiwan, Republic of China

Foreign Ag-specific TCR-transgenic (Tg) mice contain a small fraction of T cells bearing the endogenous Vβ and V chains as well as a population expressing an intermediate level of Tg TCR. Importantly, these minor nonclonotypic populations contain 99% of the CD4⁺Foxp3⁺ regulatory T cells (Treg) and, despite low overall Treg expression, peripheral tolerance is maintained. In the OT-II TCR (OVA-specific, Vβ5^highV2^high) Tg scurfy (Sf) mice (OT-II Sf) that lack Treg, nonclonotypic T cells markedly expanded in the periphery but not in the thymus. Expanded T cells expressed memory/effector phenotype and were enriched in blood and inflamed lungs. In contrast, Vβ5^highV2^high clonotypic T cells were not expanded, displayed the naive phenotype, and found mainly in the lymph nodes. Importantly, Vβ5^neg T cells were able to transfer multiorgan inflammation in Rag1^–/– recipients. T cells bearing dual TCR (dual Vβ or dual V) were demonstrated frequently in the Vβ5^int and V2^int populations. Our study demonstrated that in the absence of Treg, the lack of peripheral expansion of clonotypic T cells is due to the absence of its high-affinity Ag OVA. Thus, the rapid expansion of nonclonotypic T cells in OT-II Sf mice must require Ag (self and foreign) with sufficient affinity. Our study has implications with respect to the roles of Ag and dual TCR in the selection and regulation of Treg and Treg-controlled Ag-dependent T cell expansion in TCR Tg and TCR Tg Sf mice, respectively.

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 DE-017579 and AR-051203 (to S.-T.J.) and AR-047988 and AR-049449 (to S.M.F.) and a Grant-in-Aid from the Beirne B. Carter Center of Immunology (to R.S.).

² S.M.F. and S.-T.J. are co-senior authors and contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Shyr-Te Ju, Department of Medicine, Center for Immunity, Inflammation and Regenerative Medicine, Old Medical School Building, Room 5777, 5th floor, University of Virginia, Charlottesville, VA 22908. E-mail address: sj8r{at}virginia.edu

⁴ Abbreviations used in this paper: Tg, transgenic; Sf, scurfy; Treg, regulatory T cell; T_M/T_E, memory T/effector T; T_N, naive T; int, intermediate; neg, negative.