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 αβTCR+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.

MHC Class II Restricted Innate-Like Double Negative T Cells Contribute to Optimal Primary and Secondary Immunity to Leishmania major

“…Some reports suggest that DN T cells originate in the thymus by escaping negative selection [17], [18], [19]. In contrast, several reports suggest that DN T cells are generated in the periphery rather than in the thymus [19], [20], [21], [22]. These cells comprise about 1–5% of total T cells in non-transgenic mice and in humans [11], [23] making them difficult to isolate and subsequently study.…”

Programmed Cell Death 1 and Helios Distinguish TCR-αβ+ Double-Negative (CD4−CD8−) T Cells That Derive from Self-Reactive CD8 T Cells

“…Previous studies have suggested that they originate through a thymus-independent process (5,6). However, several lines of evidence strongly support the hypothesis that DN T cells arise from activated thymic-derived CD4 + (7,8) or CD8 + cells (9-11).…”

Hyperactive mTOR pathway promotes lymphoproliferation and abnormal differentiation in autoimmune lymphoproliferative syndrome

“…In murine transplantation models, conventional DNT cells have been shown to suppress immune responses through Fas/FasL-mediated elimination of effector T cells [48][49][50][51][52][53] Of interest, DNT cells from MRL/lpr mice, a murine model of ALPS, were shown to kill syngeneic wild-type, but not Fas-deficient, lpr CD4 1 or CD8 1 T cells, indicating that the regulatory function of DNT cells in lpr mice is retained. 48 We demonstrated recently that activation of the mTOR pathway abrogates the immunoregulatory function of DNT cells from healthy volunteers by reversing their anergic phenotype while promoting proliferation.…”