The inhibitory receptor CD200R educates ILC1s for optimal cytotoxicity

Conventional natural killer (cNK) cells are educated through inhibitory receptor engagement with MHC-? ligands, ensuring functional competence and self-tolerance. However, as a population likewise exhibiting cytotoxicity, whether type 1 innate lymphoid cells (ILC1s) undergo education and the underlying mechanisms remain unclear. Our study reveals that, CD200R, an inhibitory receptor specifically expressed by ILC1s, selectively suppresses ILC1 cytotoxicity upon CD200 engagement. Surprisingly, CD200R deficiency impairs ILC1 degranulation and cytotoxic activity without affecting inflammatory cytokine production. This defect is accompanied by compromised metabolic fitness in ILC1s. Analogous to cNK cell education, we demonstrate that CD200R educates ILC1 cytotoxicity primarily through the WNT/ß-catenin pathway. Importantly, the impaired effector functions of uneducated ILC1s could be restored by exposure to certain cytokines. Collectively, 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. Overall design: RNA-seq profiling of liver ILC1s from WT and Cd200r-/- adult mice