Transient tissue residency and lymphatic egress define human CD56bright NK cell homeostasis (scRNA-seq)

Although human tissue-resident (TR) CD56bright natural killer (NK) cells can be identified based on integrins and chemokine receptors inferred from murine studies, many aspects of their homeostasis remain elusive. Here, we used an integrated approach of dynamic human, humanized mouse, and non-human primate models and sampling of efferent lymph fluid to determine recirculation and TR patterns of human NK cells. By intravascular labelling, we show that CD56bright access tissue niches at steady state. Furthermore, in human liver transplantation, donor-derived CD56bright NK cells represent the dominant TR NK cell population early after transplantation but were replaced over time by infiltrating recipient NK cells that established tissue-resident traits, a process partly regulated by Runx3. Transient TR CD56bright NK cells recirculated via lymphatics, displaying a consistent phenotype detectable in draining lymph nodes and efferent lymph fluid, and waned from peripheral blood upon lymph node egress blockade. Finally, CD56dim NK cells, constrained to vasculature at steady state, entered lymph nodes upon inflammation. Altogether, this study provides a mechanistic framework for the transient tissue-residency and recirculation patterns of human NK cell populations.