title: Double-negative T regulatory cells can develop outside the thymus and do not mature from CD8+ T cell precursors.
abstract: Recent studies have demonstrated that activated peripheral alphabeta 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.
authors.affiliation: Multiorgan Transplantation Program, Toronto General Research Institute, University Health Network, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada.
authors.forename: Megan S
authors.initials: MS
authors.lastname: Ford
authors.forename: Zhu-Xu
authors.initials: ZX
authors.lastname: Zhang
authors.forename: Wenhao
authors.initials: W
authors.lastname: Chen
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D016827:CD8 Antigens / Q000235:genetics / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D019070:Cell Lineage; D051379:Mice; D018345:Mice, Knockout; D013234:Stem Cells / Q000166:cytology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology
chemical_list: D016827:CD8 Antigens