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

Fahlén and colleagues now attempt to define the role of TGF-ß 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-ß receptor. This demonstrated that effector cells had to be responsive to TGF-ß to be controlled by T reg cells. The T reg cells were not required as a source of TGF-ß, as T reg cells from TGF-ß–deficient mice were also able to suppress. Thus, T reg cells must be prompting another cell type to produce TGF-ß, or may be producing a regulatory signal that operates cooperatively with TGF-ß.

But did the T reg cells also require TGF-ß 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-ß receptors, and lymph node–derived T reg cells from both mice suppressed colitis.

Transfer of splenic T reg cells with mutant TGF-ß 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-ß receptor and, therefore, cannot be controlled by the inhibitory signal. Thus, the requirement for TGF-ß in T reg cell suppression appears to be dictated primarily by the effector cells.