Origin of Hypofunctional CD103+ NK Cells in Cirrhosis-Associated Ascites

Abstract

The occurrence of ascites is a frequent complication associated with the decompensation of liver cirrhosis. While it is known that cirrhosis leads to altered immune responses in the periphery, the immunological milieu of ascites remains poorly understood. In this study, we investigate the role and origin of natural killer (NK) cells in cirrhosis-associated ascites. Using high-dimensional flow cytometry and cytokine analysis, we analyzed matched peripheral blood and ascites fluid alongside liver and duodenum samples to discern tissue-specific differences. Interestingly, a subset of peritoneal NK cells displayed high expression of the tissue-residency receptor CD103. This subset of CD103⁺ ascites NK cells was distinct from blood, liver, and intestinal NK cells and presented with a less activated phenotype coupled with reduced effector capacity. Investigating their origin, we could identify that cytokines present in ascites, here predominantly IL-15 in synergy with IL-21 and TGFβ, can induce CD103 expression and that ascites supernatant further facilitates this process. These results indicate that the ascites in patients with decompensated liver cirrhosis harbor a heterogenous subset of CD103⁺ NK cells that is likely induced by the cytokine milieu.