Limited recirculation of cytotoxic NK cells during normal homeostasis in humans

Abstract Natural killer (NK) cells are well known for their cytolytic functions to directly kill virus-infected and malignant cells. Two major NK cell populations exist in humans: Cytotoxic CD56dim and immunoregulatory CD56bright NK cells. Although NK cells are distributed throughout the human body, little is known about which NK cell populations that traffic tissues and egress from tissues to recirculate back to blood. Here, we set outto determine the recirculation patterns of human NK cell subsets during normal homeostasis through access to multiple types of tissues, blood, and thoracic duct lymph (TDL). Whereas cytotoxic NK cells were dominant in peripheral blood, non-lymphoid tissues (liver, uterus, duodenum, adipose tissue) were enriched for immunoregulatory NK cells expressing markers of tissue-residency. Similarly, few cytotoxic NK cells were present in secondary lymphoid organs and efferent lymph (TDL). Instead, afferent and efferent venous blood of human liver was similar in NK cell subset composition as peripheral blood, suggesting that cytotoxic NK cells are retained in vasculature during steady-state. Ongoing mechanistic efforts include assessment of NK cell subsets in patients before and after blocking cellular egress from tissues with FTY-720 (S1PR agonist) treatment. These results offer a revised model for NK cell subset trafficking behavior and suggests that cytotoxic NK cells have limited access to peripheral tissues during normal homeostasis.