Refusing to be suppressed

On page 737, Fahlén et al. show that colitis-inducing effector T cells that cannot respond to the suppressive cytokine TGFrefuse 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. TGFappears to be required for T reg cell activity, but determining which cells produce TGFand which cells respond to it has proven difficult. Fahlén and colleagues now attempt to define the role of TGFin 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 TGFreceptor. This demonstrated that effector cells had to be responsive to TGFto be controlled by T reg cells. The T reg cells were not required as a source of TGF, as T reg cells from TGF–deficient mice were also able to suppress. Thus, T reg cells must be prompting another cell type to produce TGF, or may be producing a regulatory signal that operates cooperatively with TGF. But did the T reg cells also require TGFsignals 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 TGFreceptors, and lymph node–derived T reg cells from both mice suppressed colitis. Transfer of splenic T reg cells with mutant TGFreceptors, however, triggered rather than inhibited colitis. The authors suggest that this can be explained by contaminating effector cells that are also mutant for the TGFreceptor and, therefore, cannot be controlled by the inhibitory signal. Thus, the requirement for TGFin T reg cell suppression appears to be dictated primarily by the effector cells. T reg cells cannot control colitis if the diseaseinducing effector T cells are unresponsive to TGF. Out with the old, in with the new