Human intrahepatic tregs are functional, require IL-2 from effector cells for survival and are susceptible to fas ligand mediated apoptosis

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Authors

Abstract

Regulatory T cells (Treg ) suppress T effector cell proliferation and maintain immune homeostasis. Autoimmune liver diseases (AILD) persist despite high frequencies of Treg in the liver suggesting that the local hepatic-microenvironment might affect Treg stability, survival or function. We hypothesized that interactions between Treg and endothelial cells during recruitment and then with epithelial cells within the liver affect Treg stability, survival and function. To model this we explored the function of Treg after migration through human hepatic sinusoidal-endothelium (post-endothelial migrated or PEMTreg ) and the effect of subsequent interactions with cholangiocytes and local proinflammatory cytokines on survival and stability of Treg . Our findings suggest that the intrahepatic-microenvironment is highly enriched with proinflammatory cytokines but deficient in the Treg -survival-cytokine IL-2. Migration through endothelium into a model mimicking the inflamed liver microenvironment did not affect Treg stability, however functional capacity was reduced. Furthermore, the addition of exogenous Il-2 enhanced PEMTreg phosphoSTAT5 signaling compared with PEMCD8. CD4 and CD8 T cells are the main source of IL-2 in the inflamed liver. Liver infiltrating Tregs reside close to bile ducts and co-culture with cholangiocytes or their supernatants induced preferential apoptosis of Treg compared to CD8 effector cells. Treg from diseased livers expressed high levels of CD95 and their apoptosis was inhibited by IL-2 or blockade of CD95.

CONCLUSIONS: Recruitment through endothelium does not impair Treg stability but a pro-inflammatory microenvironment, deficient in IL-2 leads to impaired function and increased susceptibility of Treg to epithelial cell-induced FAS-mediated apoptosis. These results provide a mechanism to explain Treg dysfunction in inflamed tissues and suggest that IL-2 supplementation, particularly if used in conjunction with Treg therapy, could restore immune homeostasis in inflammatory and AILD. This article is protected by copyright. All rights reserved.

Details

Original languageEnglish
Pages (from-to)138–150
JournalHepatology
Volume64
Issue number1
Early online date15 Apr 2016
Publication statusPublished - 22 Jun 2016

Keywords

  • Liver microenvironment, Regulatory T cell, biliary , epithelium, FAS, IL-2, phosphorylated STAT5