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 TGFβ.
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