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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 Tregg 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 TTreg 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 Treg reside close to bile ducts and co-culture with cholangiocytes or their supernatants induced preferential apoptosis of TTreg 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.
CONCLUSION: 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.
|Number of pages||13|
|Early online date||29 Feb 2016|
|Publication status||Published - Jul 2016|
- Liver microenvironment
- Regulatory T cell
- phosphorylated STAT5
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- 2 Finished
MRC Centre For Immune Regulation (Linked to DCDF.RRAK10540) (Linked to 14810 & 14835)
3/08/09 → 30/09/17
Project: Research Councils