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Double-Negative T Regulatory Cells Can Develop Outside the Thymus and Do Not Mature from CD8⁺ T Cell Precursors¹

Megan S. Ford^2,*, Zhu-Xu Zhang^2,3,*, Wenhao Chen^* and Li Zhang^4,*,

^* Multiorgan Transplantation Program, Toronto General Research Institute, University Health Network, and Departments of Laboratory Medicine and Pathobiology, and Immunology, University of Toronto, Toronto, Ontario, Canada

Recent studies have demonstrated that activated peripheral TCR⁺CD3⁺CD4^–CD8^–NK1.1^– (double-negative, DN) regulatory T cells (Tregs) from both mice and humans are able to down-regulate immune responses in vitro and in vivo. However, the origin and developmental requirements of functional DN Tregs remain unclear. In this study, we investigated the requirement for CD8 expression as well as the presence of a thymus for the development of functional DN Tregs. We demonstrate that DN Tregs exist in CD8-deficient mice and that stimulation of CD8⁺ T cells in vivo with TCR-specific Ag does not convert CD8⁺ T cells into DN Tregs. In addition, we found that DN T cells are present in the spleens and lymph nodes of thymectomized mice that are irradiated and reconstituted with T cell-depleted bone marrow cells. Interestingly, DN Tregs that develop in thymectomized mice can suppress syngeneic CD8⁺ T cells more effectively than those that develop in sham-thymectomized mice. Taken together, our data suggest that DN Tregs are not derived from CD8⁺ T cell precursors and that functional DN Tregs may preferentially develop outside of the thymus. These data suggest that DN Tregs may represent a developmentally and functionally unique cell population.

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 is supported by Canadian Institutes of Health Research Grant MOP 14431 and National Cancer Institute of Canada Grant 15067 (to L.Z.). Additional funding is provided by Wyeth-Ayerst Canada.

² M.S.F. and Z.-X.Z. contributed equally to this paper.

³ Current address: Department of Surgery, University of Western Ontario, London, Ontario, Canada.

⁴ Address correspondence and reprint requests to Dr. Li Zhang, Toronto General Research Institute, University Health Network, 101 College Street, TMDT 2-807, Toronto, Ontario M5G 1L7, Canada. E-mail address: lzhang{at}uhnres.utoronto.ca

⁵ Abbreviations used in this paper: Treg, regulatory T cell; DN, double negative; NALT, nasal-associated lymphoid tissue; Tg, transgenic; DLI, donor lymphocyte infusion.

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