The inhibitory receptor CD200R educates ILC1s for optimal cytotoxicity

• 成果类型: Article
• 署名作者: Chen, Yawen; Zhang, Zhengfeng; Wang, Xianwei; Zheng, Xiaodong; Chen, Yongyan; Sun, Rui; Sun, Haoyu; Tian, Zhigang; Peng, Hui
• 署名单位: Chinese Academy of Sciences; University of Science & Technology of China, CAS; Fudan University; Fudan University; Fudan University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2532767123
• 发表日期: 2026-08-18
• 页码: e2532767123
• 关键词: ILC1s; cytotoxicity; education; CD200R; innate lymphoid-cells; NATURAL-KILLER-CELLS; mhc class-i; beta-catenin; nk cells; wnt; homeostasis; self

摘要

Conventional natural killer (cNK) cells are educated through inhibitory receptor engagement with MHC-I ligands, which endows them with potent cytotoxicity and robust IFN-gamma 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-gamma production. Unlike cNK cells, ILC1 cytotoxicity remains intact in mice lacking MHC-I molecules, and IFN-gamma 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-gamma production. Analogous to cNK cell education, CD200R educates ILC1 cytotoxicity primarily through the WNT/beta-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.