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

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. Here 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 naïve 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 novel aspects of CCR8 signaling regulated ILC2 motility and function, especially in the skin, in response to two hallmark ILC2 activating alarmins.