Development of regulatory IL-10-producing ILCs during type 2 inflammation

Abstract

Abstract Innate lymphoid cells (ILCs) are important for mucosal homeostasis and host defense against infectious pathogens. ILC subsets ILC1, 2, and 3, classified similar to T helper cells Th1, Th2, and Th17, are well characterized and known to promote both protective and harmful inflammatory responses. However, the immunosuppressive roles of ILCs are less understood. Regulatory ILCs that produce the immunomodulatory cytokine IL-10 have been recently defined, but the mechanisms regulating their development and function are not fully understood. Similar to other ILCs, regulatory ILCs were thought to be a pre-existing population, however unlike ILC1, 2, and 3 which all differentiate from ILC precursor cells (ILCPs), regulatory ILCs were thought to differentiate exclusively from upstream precursors, common helper-like innate lymphoid precursors (CHILPs) and common lymphoid cell precursors (CLPs). In our animal facilities, we found no evidence of pre-existing tissue resident IL-10+ ILCs in our investigations. In contrast, we find that co-stimulation of IL-33 and a γ-chain cytokine (IL-2, IL-4, or IL-7) robustly induces IL-10+ILCs that exhibit immunosuppressive functions in vitro and in vivo. Further, in addition to CLPs and CHILPs, we find that downstream ILC2Ps can develop into functionally suppressive IL-10+ ILCs following cytokine stimulation. Together, our data support an alternative pathway of IL-10-producing regulatory ILC development and regulation of inflammatory responses.