IL-33 Receptor-Expressing Regulatory T Cells Are Highly Activated, Th2 Biased and Suppress CD4 T Cell Proliferation through IL-10 and TGFß Release

Immunomodulatory Foxp3+ regulatory T cells (Tregs) form a heterogeneous population consisting of subsets with different activation states migratory properties and suppressive functions. Recently expression of the IL 33 receptor ST2 was shown on Tregs in inflammatory settings. Here we report that ST2 expression identifies highly activated Tregs in mice even under homeostatic conditions. ST2+ Tregs preferentially accumulate at non lymphoid sites likely mediated by their high expression of several chemokine receptors facilitating tissue homing. ST2+ Tregs exhibit a Th2 biased character expressing GATA 3 and producing the Th2 cytokines IL 5 and IL 13 –especially in response to IL 33. Yet IL 33 is dispensable for the generation and maintenance of these cells in vivo. Furthermore ST2+ Tregs are superior to ST2- Tregs in suppressing CD4+ T cell proliferation in vitro independent of IL 33. This higher suppressive capacity is partially mediated by enhanced production and activation of the anti inflammatory cytokines IL 10 and TGFß. Thus ST2 expression identifies a highly activated strongly suppressive Treg subset preferentially located in non lymphoid tissues. Here ST2+ Tregs may be well positioned to immediately react to IL 33 alarm signals. Their specific properties may render ST2+ Tregs useful targets for immunomodulatory therapies.