CD127+ Natural Killer Cells Represent a Distinct, Interleukin-15-Independent and Thymus-Independent Subset in Mice

Natural killer (NK) cells, key effectors of innate immunity, are classically categorized into CD56dim and CD56bright subsets in humans. While murine NK cell heterogeneity has become increasingly recognized, the classification of mature NK cell subsets remains incompletely defined. Here, we comprehensively characterized CD127+ NK cells in mice and identified them as a distinct, mature subset, developing independently of the thymus and interleukin (IL)-15 signaling. Flow cytometric analyses revealed that CD127+ NK cells are broadly distributed across lymphoid and non-lymphoid tissues—including in C57BL/6 wild-type and athymic Foxn1−/− mice—and exhibit a surface phenotype distinct from CD127− NK and thymus-derived CD127+ NK cells. Functional assays demonstrated that CD127+ NK cells produce interferon-γ and exert cytotoxic activity, despite expressing markers typically associated with immature NK cells. CD127+ NK cells were absent in IL-7Rα−/− mice but present in IL-15−/− and IL-15Rα−/− mice, indicating a selective dependence on IL-7 signaling. IL-7 promoted their proliferation and activation both in vitro and in vivo. These findings revise current models of NK cell development by identifying a novel, IL-7-responsive, IL-15-independent, thymus-independent, and functionally competent CD127+ NK cell subset that is phenotypically distinct from helper-like innate lymphoid cells (ILCs). This study provides a framework for future investigations on NK cell heterogeneity, tissue specialization, and cytokine-mediated regulation.