Tissue driven influences on human NK cell development, function and residence

Abstract

Abstract Natural killer (NK) cells are innate immune cells with the inherent ability to kill tumor and virus infected cells without any prior priming. Recent studies have demonstrated the ability of NK cells to develop adaptive memory and tissue residence. However, our understanding of human NK cells in tissues and their site-specific properties is limited. Here we use our unique tissue resource established in collaboration with LiveOnNY to elucidate the diversity of human NK cell phenotypic subsets, functional profile and transcriptional signatures in non-mucosal and mucosal tissue sites. We identified tissue-specific patterns of NK cell maturation and show that NK cell subset (immature and mature) and memory NK cell distribution is a function of tissue site which is not affected by age. Our results also show that while NK cells from different tissue sites express similar levels of granzyme B, NK cell antibody-dependent cellular cytotoxicity response and cytokine driven activation may be influenced by tissue site. Whole transcriptome profiling of NK cell subsets revealed that mature NK cells from all the sites (blood, bone marrow, spleen, lung and LN) have very similar transcriptional profiles. Interestingly, immature NK cells from all tissue sites have very different transcriptional profiles compared to their blood counterpart and are enriched for tissue resident memory T cell transcriptional signature. Furthermore, we show that immature NK cells show site-specific expression patterns of tissue residence surface markers. Overall, our data demonstrates the effects of tissue microenvironment on the developmental and function potential of tissue NK cells and provides insight into the development of future NK cell mediated immunotherapies.