Type I interferon limits ILC2 effector functions through suppression of the CCR8-CCL1/CCL8 axis

Group 2 innate lymphoid cells (ILC2s) exert critical roles in anti-helminth immunity and the pathogenesis of allergic diseases by rapidly secreting vast amounts of type 2 signature cytokines. Type 1 interferons (IFN-I) are critical negative regulators of ILC2 effector functions and associated innate and adaptive type 2 immunopathologies. Exposure to IFN-I inhibits ILC2 proliferation as well as type 2 cytokine production, however, the mechanistic underpinnings of IFN-I-mediated ILC2 regulation remain largely elusive. Using RNA-sequencing analysis, we demonstrate that IFN-I treatment inhibits the production of the chemokine CCL1 by ILC2s. Moreover, expression of CCR8, the cognate chemokine receptor for CCL1, is downregulated upon IFN-I-stimulation ex vivo as well as in vivo upon sublethal influenza A virus infection (IAV) or upon IFN-I administration following pulmonary IL-33 challenge. In addition, expression of CCL8, the chemotactic ligand of CCR8, was suppressed in an IFN-I dependent manner in the lungs of IAV-infected mice. IFN-b potently restrained pulmonary CCL1/CCL8 expression as well as CCR8 expression by ILC2 and CD4+ T cells in a model of IL-33-driven allergic airway inflammation. Thus, this study sheds new light on the underlying mechanisms of ILC2 regulation by identifying the CCR8-CCL1/CCL8 axis as a target for IFN-I-driven ILC2 inhibition. Overall design: Murine lun ILC2 were isolated and stimulated or not for 4h or 24h with rmIL33 and/or IFNb. The transcriptional response was analyzed by RNA sequencing.