STAT6 activation confers upon T helper cells resistance to suppression by regulatory T cells.
ABSTRACT Recent studies have highlighted characteristics of T regulatory cells (Tregs) that underlie their suppressive function. However, mechanisms that override their suppressive function in the context of an adaptive immune response are not well understood. In the lungs of mice undergoing allergic inflammation, appreciable numbers of Tregs were identified that possessed suppressive function when assayed ex vivo. We investigated whether the Th2-promoting cytokine IL-4 played a permissive role that superseded Treg function, thereby allowing the development of allergic inflammation. IL-4 signaling via the IL-4Ralpha-STAT6 axis was required to maintain Foxp3 expression in Tregs and promote their proliferation. However, the results of both in vivo experiments involving adoptive transfer of Tregs into Ag-sensitized vs naive animals and in vitro suppression assays performed with or without exogenous IL-4 showed the ability of IL-4 to compromise Treg-mediated suppression. Use of retrovirally expressed, constitutively active STAT6 revealed that the underlying mechanism was not IL-4-mediated dysfunction of Tregs but involved the resistance of Th cells to Treg-mediated suppression that would permit the development of an adaptive immune response. Our data suggest that infectious tolerance, mediated by membrane-bound TGF-beta expressed by Tregs, is compromised by the competing effects of IL4-induced signaling in naive CD4(+) Th cells.
Article: Cell contact-dependent immunosuppression by CD4(+)CD25(+) regulatory T cells is mediated by cell surface-bound transforming growth factor beta.[show abstract] [hide abstract]
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)-beta1 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-beta1 (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-beta. In addition, we found that CD4(+)CD25(+) T cells suppress B cell immunoglobulin production and that anti-TGF-beta 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-beta1 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-beta1.Journal of Experimental Medicine 10/2001; 194(5):629-44. · 13.85 Impact Factor