Human intrahepatic regulatory T cells are functional, require IL‐2 from effector cells for survival, and are susceptible to Fas ligand‐mediated apoptosis

Regulatory T cells (T(reg)) suppress T effector cell proliferation and maintain immune homeostasis. Autoimmune liver diseases persist despite high frequencies of T(reg) in the liver, suggesting that the local hepatic microenvironment might affect T(reg) stability, survival, and function. We hypothesized that interactions between T(reg) and endothelial cells during recruitment and then with epithelial cells within the liver affect T(reg) stability, survival, and function. To model this, we explored the function of T(reg) after migration through human hepatic sinusoidal‐endothelium (postendothelial migrated T(reg) [PEM T(reg)]) and the effect of subsequent interactions with cholangiocytes and local proinflammatory cytokines on survival and stability of T(reg). Our findings suggest that the intrahepatic microenvironment is highly enriched with proinflammatory cytokines but deficient in the T(reg) survival cytokine interleukin (IL)‐2. Migration through endothelium into a model mimicking the inflamed liver microenvironment did not affect T(reg) stability; however, functional capacity was reduced. Furthermore, the addition of exogenous IL‐2 enhanced PEM T(reg) phosphorylated STAT5 signaling compared with PEMCD8. CD4 and CD8 T cells are the main source of IL‐2 in the inflamed liver. Liver‐infiltrating T(reg) reside close to bile ducts and coculture with cholangiocytes or their supernatants induced preferential apoptosis of T(reg) compared with CD8 effector cells. T(reg) from diseased livers expressed high levels of CD95, and their apoptosis was inhibited by IL‐2 or blockade of CD95. Conclusion: Recruitment through endothelium does not impair T(reg) stability, but a proinflammatory microenvironment deficient in IL‐2 leads to impaired function and increased susceptibility of T(reg) to epithelial cell‐induced Fas‐mediated apoptosis. These results provide a mechanism to explain T(reg) dysfunction in inflamed tissues and suggest that IL‐2 supplementation, particularly if used in conjunction with T(reg) therapy, could restore immune homeostasis in inflammatory and autoimmune liver disease. (Hepatology 2016;64:138–150)