The inhibitory receptor CD200R educates ILC1s for optimal cytotoxicity

Conventional natural killer (cNK) cells are educated through inhibitory receptor engagement with MHC-I ligands, which endows them with potent cytotoxicity and robust IFN-γ production. Although type 1 innate lymphoid cells (ILC1s) exhibit analogous functionality, whether they undergo a similar education process remains unclear. Our study reveals that the inhibitory receptor CD200R educates ILC1s for optimal cytotoxic competence but is dispensable for IFN-γ production. Unlike cNK cells, ILC1 cytotoxicity remains intact in mice lacking MHC-I molecules, and IFN-γ production shows only a limited, context-dependent reduction. While CD200R selectively suppresses ILC1 cytotoxicity upon CD200 engagement in vitro, ILC1s from CD200R-deficient mice exhibit impaired degranulation and cytotoxic activity, with unaltered IFN-γ production. Analogous to cNK cell education, CD200R educates ILC1 cytotoxicity primarily through the WNT/β-catenin pathway. Importantly, the impaired effector functions of uneducated ILC1s could be restored by exposure to inflammatory cytokines. Overall, our study defines a critical role for the inhibitory receptor CD200R in educating ILC1s to achieve cytotoxic maturity, revealing a parallel yet distinct mechanism from cNK cell education.