CD200R1 Marks a Branchpoint During Human Natural Killer Cell Development in Tonsils

Human natural killer (NK) cells arise from common innate lymphoid cell (ILC) progenitor and precursor populations that are selectively enriched within secondary lymphoid tissues (SLTs) and that complete their terminal differentiation through stages of progressively lineage-restricted downstream developmental intermediates. We identify two subsets of tonsil CD94/NKG2A+NKp80- (stage 4A) NK-cell development intermediates that show differential expression of the inhibitory receptor, CD200R1. Ex vivo single-cell transcriptomic, DNA methylation, phenotypic, and functional analyses demonstrate that CD200R1⁺ stage 4A cells represent an immature, oligopotent precursor population enriched for tissue-resident and cytokine-responsive programs. In contrast, CD200R1⁻ stage 4A cells show more restricted NK-cell developmental potential concomitant with features of mature NK cells. These findings help to refine the human NK cell developmental pathway in tonsils and highlight CD200R1 as a useful marker delineating an uncommitted developmental state linking microenvironmental cues to NK-cell maturation and plasticity.