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

Abstract

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.

IL‐10‐producing, ST2‐expressing Foxp3+ T cells in multiple sclerosis brain lesions

“…Expression of the IL-33 receptor, ST2, has been associated with potent Treg function in murine models. [24][25][26] Indeed, we found ST2 to be particularly enriched in CNS Treg in EAE (Figure 4a). IL-33 is highly expressed in the CNS in both EAE and MS ( Figure 4b).…”

The atopic march: current insights into skin barrier dysfunction and epithelial cell‐derived cytokines

“…ST2 was first shown to be selectively expressed by Th2 cells . Later studies found ST2 expression on other cell types, including macrophages, dendritic cells, basophils, mast cells, regulatory T cells, and ILC2s . IL‐33 can drive eosinophil differentiation from bone marrow precursors in vitro and stimulate cytokine production in eosinophils and mast cells .…”

Immune‐ and non‐immune‐mediated roles of regulatory T‐cells during wound healing

“…However, alternatively, T reg ‐derived Amphiregulin may also contribute to the survival and expansion of tissue‐resident T regs upon injury. Because it was also further shown that T1/ST2‐expressing T reg populations preferentially express high levels of integrin‐ α V and low levels of IL‐10, it is tempting to speculate that this constitutive expression of Amphiregulin by tissue‐resident T regs may also lead to a constitutive, low‐level release of bio‐active TGF β , which may contribute to ongoing regeneration of tissues and to a low‐level immune‐suppressive environment in the surrounding of Amphiregulin‐expressing tissue‐resident T reg populations, which might be an evolutionary advantage for instance in inflammation‐prone tissues, such as fatty tissues.…”

“…Amphiregulin‐expressing T regs are typically restricted to tissue‐resident T reg populations and thus suggest an organ‐specific role for T reg ‐expressed Amphiregulin . These tissue‐resident T reg populations also preferentially express the IL‐33 receptor, T1/ST2 . The role of T1/ST2 expression on T regs currently remains unresolved.…”