Piersma Sytse J, Li Shasha, Wong Pamela, Bern Michael D, Poursine-Laurent Jennifer, Yang Liping, Beckman Diana L, Parikh Bijal A, Yokoyama Wayne M
Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St Louis, United States.
Siteman Cancer Center, Washington University School of Medicine, St Louis, United States.
Elife. 2025 Mar 14;13:RP100218. doi: 10.7554/eLife.100218.
Natural killer (NK) cells recognize target cells through germline-encoded activation and inhibitory receptors enabling effective immunity against viruses and cancer. The Ly49 receptor family in the mouse and killer immunoglobin-like receptor family in humans play a central role in NK cell immunity through recognition of major histocompatibility complex class I (MHC-I) and related molecules. Functionally, these receptor families are involved in the licensing and rejection of MHC-I-deficient cells through missing-self. The Ly49 family is highly polymorphic, making it challenging to detail the contributions of individual Ly49 receptors to NK cell function. Herein, we showed mice lacking expression of all Ly49s were unable to reject missing-self target cells in vivo, were defective in NK cell licensing, and displayed lower KLRG1 on the surface of NK cells. Expression of Ly49A alone on an H-2D background restored missing-self target cell rejection, NK cell licensing, and NK cell KLRG1 expression. Thus, a single inhibitory Ly49 receptor is sufficient to license NK cells and mediate missing-self in vivo.
自然杀伤（NK）细胞通过种系编码的激活和抑制性受体识别靶细胞，从而实现对病毒和癌症的有效免疫。小鼠中的Ly49受体家族和人类中的杀伤性免疫球蛋白样受体家族通过识别主要组织相容性复合体I类（MHC-I）及相关分子，在NK细胞免疫中发挥核心作用。在功能上，这些受体家族通过“缺失自我”机制参与MHC-I缺陷细胞的许可和排斥。Ly49家族具有高度多态性，这使得详细阐述单个Ly49受体对NK细胞功能的贡献具有挑战性。在此，我们表明缺乏所有Ly49表达的小鼠在体内无法排斥“缺失自我”靶细胞，NK细胞许可存在缺陷，并且NK细胞表面的KLRG1表达较低。在H-2D背景下单独表达Ly49A可恢复“缺失自我”靶细胞排斥、NK细胞许可以及NK细胞KLRG1表达。因此，单个抑制性Ly49受体足以许可NK细胞并在体内介导“缺失自我”机制。
