Cutting Edge: CCR8 Signaling Regulates IL-25– and IL-33–Responsive Skin Group 2 Innate Lymphoid Cell Migration and Function

Abstract Group 2 innate lymphoid cells (ILC2s) are sentinels of barrier immunity, and their activation by the epithelial alarmins IL-25 and IL-33 is a defining trait. In this study, we identified a role for the chemokine receptor CCR8 in modulating skin ILC2 abundance and activation. CCR8 signaling facilitated IL-25–induced increases in skin and lung ILC2s, ILC2 activation and systemic IL-13 production, and ligand-directed ILC2 entry into skin and lung. CCR8 controlled ILC2 tissue entry in IL-25–treated naive mice, but only transferred bone marrow ILC2 progenitors were equipped to enter the skin, whereas multiple tissue-sourced ILC2s entered the lung. CCR8 selectively regulated IL-33–induced increases in skin ILC2s, their proliferation, and production of IL-13/IL-5, as well as IL-33–responsive transferred ILC2 trafficking only to the skin. Collectively, we illuminate (to our knowledge) novel aspects of CCR8 signaling-regulated ILC2 motility and function, especially in the skin, in response to two hallmark ILC2-activating alarmins.