Human intrahepatic 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 (AILD) persist despite high frequencies of T_reg in the liver suggesting that the local hepatic-microenvironment might affect T_regg stability, survival or 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 (post-endothelial migrated or PEMT_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 IL-2. Migration through endothelium into a model mimicking the inflamed liver microenvironment did not affect TT_reg stability, however functional capacity was reduced. Furthermore, the addition of exogenous Il-2 enhanced PEMT_reg phosphoSTAT5 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 co-culture with cholangiocytes or their supernatants induced preferential apoptosis of TT_reg compared to 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 pro-inflammatory 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 AILD.