Cell Contact–Dependent Immunosuppression by Cd4 ⁺Cd25 ⁺Regulatory T Cells Is Mediated by Cell Surface–Bound Transforming Growth Factor β

Abstract

CD4 ⁺CD25 ⁺ T cells have been identified as a population of immunoregulatory T cells, which mediate suppression of CD4 ⁺CD25 ⁻ T cells by cell–cell contact and not secretion of suppressor cytokines. In this study, we demonstrated that CD4 ⁺CD25 ⁺ T cells do produce high levels of transforming growth factor (TGF)-β1 and interleukin (IL)-10 compared with CD4 ⁺CD25 ⁻ T cells when stimulated by plate-bound anti-CD3 and soluble anti-CD28 and/or IL-2, and secretion of TGF-β1 (but not other cytokines), is further enhanced by costimulation via cytotoxic T lymphocyte–associated antigen (CTLA)-4. As in prior studies, we found that CD4 ⁺CD25 ⁺ T cells suppress proliferation of CD4 ⁺CD25 ⁻ T cells; however, we observed here that such suppression is abolished by the presence of anti–TGF-β. In addition, we found that CD4 ⁺CD25 ⁺ T cells suppress B cell immunoglobulin production and that anti–TGF-β again abolishes such suppression. Finally, we found that stimulated CD4 ⁺CD25 ⁺ T cells but not CD4 ⁺CD25 ⁻ T cells express high and persistent levels of TGF-β1 on the cell surface. This, plus the fact that we could find no evidence that a soluble factor mediates suppression, strongly suggests that CD4 ⁺CD25 ⁺ T cells exert immunosuppression by a cell–cell interaction involving cell surface TGF-β1.