T reg cells cannot control colitis if the disease-inducing effector T cells are unresponsive to TGF-β.

On page 737, Fahlén et al. show that colitis-inducing effector T cells that cannot respond to the suppressive cytokine TGF-β refuse to be controlled by regulatory T (T reg) cells.Naturally occurring T reg cells suppress the activity of effector CD4+ T cells and are essential for the prevention of autoimmune disease and chronic inflammation. TGF-β appears to be required for T reg cell activity, but determining which cells produce TGF-β and which cells respond to it has proven difficult.

Fahlén and colleagues now attempt to define the role of TGF-β in a mouse model of T cell–induced colitis. In this model, colitis can be reversed when CD4+CD25+ T reg cells are provided along with the disease-inducing effector cells. The authors showed that wild-type T reg cells inhibited the development of colitis induced by wild-type effector T cells but failed to prevent disease caused by effector T cells bearing a signaling-defective TGF-β receptor. This demonstrated that effector cells had to be responsive to TGF-β to be controlled by T reg cells. The T reg cells were not required as a source of TGF-β, as T reg cells from TGF-β–deficient mice were also able to suppress. Thus, T reg cells must be prompting another cell type to produce TGF-β, or may be producing a regulatory signal that operates cooperatively with TGF-β.

But did the T reg cells also require TGF-β signals to induce suppression, as several previous studies had shown? The authors found no differences between the T reg populations in mice with normal or signaling-defective TGF-β receptors, and lymph node–derived T reg cells from both mice suppressed colitis.

Transfer of splenic T reg cells with mutant TGF-β receptors, however, triggered rather than inhibited colitis. The authors suggest that this can be explained by contaminating effector cells that are also mutant for the TGF-β receptor and, therefore, cannot be controlled by the inhibitory signal. Thus, the requirement for TGF-β in T reg cell suppression appears to be dictated primarily by the effector cells.