Regulatory T (T reg) cells suppress other T cells in part via the cytokine TGF-β, which can convert naïve CD4+ T cells into suppressor cells. Andersson et al. now find that naïve CD4+ T cells turn into suppressor cells only when they bump into T reg cells that have an inactive TGF-β complex on their surface. Proteolysis of the inactive complex, which liberates soluble protein, was required for conversion. Inhibiting the protease or swamping the cells with inactive complex prevented cleavage and thus conversion. The converted cells could suppress gut inflammation when transferred into mice suffering from colitis.
Other immune cells also secrete soluble TGF-β, but they do not seem to force conversion—at least in this system. Previous experiments showed that naïve T cells cultured with T reg cell–depleted spleen cells, which secrete TGFβ, fail to convert. Non-T reg cells don't express the inactive surface complex, so perhaps its cleavage is needed to trigger other conversion-supporting signals.
The latent TGF-β complex was present only on T reg cells that had been stimulated via their T cell receptors. This specificity might allow T reg cells to limit conversion by delivering the TGF-β signal only to T cells bound to the same antigen-presenting cell and thus on the verge of being activated. “We wouldn't want T reg cells to run amok and convert all naïve T cells,” says lead author Ethan Shevach. How often T reg cells rely on this mechanism and its impact on the induction of tolerance in vivo are unknown.