Semaphorin 6D-expressing mesenchymal cells regulate IL-10 production by ILC2s in the lung

Group 2 innate lymphoid cells (ILC2s) have been implicated in both physiologic tissue remodeling and allergic pathology, yet the niche signaling required for ILC2 properties is poorly understood. Here, we show that an axonal guidance cue semaphorin 6D (Sema6D) plays critical roles in the maintenance of IL-10-producing ILC2s. Sema6d mice exhibit a severe steady-state reduction in ILC2s in peripheral sites such as the lung, visceral adipose tissue, and mesentery. Interestingly, loss of Sema6D results in suppressed alarmin-driven type 2 cytokine production but increased IL-10 production by lung ILC2s both in vitro and in vivo. Consequently, Sema6d mice are resistant to the development of allergic lung inflammation. We further found that lung mesenchymal cells highly express Sema6D, and that niche-derived Sema6D is responsible for these phenotypes through plexin A1. Collectively, these findings suggest that niche-derived Sema6D is implicated in physiological and pathological characteristics of ILC2s.