Immune responses show a high degree of tissue specificity shaped by factors influencing tissue egress and retention of immune cells. The transcription factor Hobit was recently shown to regulate tissue-residency in mice. Whether Hobit acts in a similar capacity in humans remains unknown. Our aim was to assess the expression and contribution of Hobit to tissue-residency of Natural Killer (NK) cells in the human liver. The human liver was enriched for CD56bright NK cells showing increased expression levels of the transcription factor Hobit. Hobitpos CD56bright NK cells in the liver exhibited high levels of CD49a, CXCR6 and CD69. Hobitpos CD56bright NK cells in the liver furthermore expressed a unique set of transcription factors with higher frequencies and levels of T-bet and Blimp-1 when compared to Hobitneg CD56bright NK cells. Taken together, we show that the transcription factor Hobit identifies a subset of NK cells in human livers that express a distinct set of adhesion molecules and chemokine receptors consistent with tissue residency. These data suggest that Hobit is involved in regulating tissue-residency of human intrahepatic CD56bright NK cells in a subset of NK cells in inflamed livers.

The recruitment and retention of Natural Killer (NK) cells in the liver are thought to play an important role during hepatotropic infections and liver cirrhosis. The aims of this study were to determine differences between liver-derived and peripheral blood-derived NK cells in the context of liver inflammation and cirrhosis. We conducted a prospective dual-center cross-sectional study in patients undergoing liver transplantation or tumor-free liver resections, in which both liver tissue and peripheral blood samples were obtained from each consenting study participants. Intrahepatic lymphocytes and PBMCs were stained, fixed and analyzed by flow cytometry. Our results showed that, within cirrhotic liver samples, intrahepatic NK cells were particularly enriched for CD49a+ NK cells when compared to tumor-free liver resection samples. CD49a+ liver-derived NK cells included populations of cells expressing CD25, CD34 and CXCR3. Moreover, CD49a+CD25+ liver-derived NK cells exhibited high proliferative capacity in vitro in response to low doses of IL-2. Our study identified a specific subset of CD49a+CD25+ NK cells in cirrhotic livers bearing functional features of proliferation.