Tissue determinants of human NK cell development, function and residence

Immune responses in diverse tissue sites are critical for protective immunity and homeostasis. Here, we investigated how tissue localization regulates the development and function of human Natural Killer (NK) cells, an innate lymphocyte important for anti-viral and tumor immunity. Integrating high dimensional analysis of NK cells from blood, lymphoid organs and mucosal tissue sites from 48 individuals, we identify tissue-specific patterns of NK cell subset distribution, maturation and function across age and genetic diversity. Mature and terminally differentiated NK cells with enhanced effector function predominate in blood, bone marrow, spleen and lungs, exhibiting shared transcriptional programs across sites. By contrast, precursor and immature NK cells with reduced effector capacity prevail in lymph nodes and intestines, exhibiting tissue resident signatures and site-specific adaptations. Together, our results reveal anatomic control of NK cell development and maintenance as tissue resident populations, while mature, terminally differentiated subsets mediate immunosurveillance through diverse peripheral sites. Overall design: mRNA profiling of CD56brightCD16- and CD56dimCD16+ NK cells from blood, bone marrow (BM), spleen, lung, lung lymph node (LN) from 4 individual donors.