Premium
Human intrahepatic regulatory T cells are functional, require IL‐2 from effector cells for survival, and are susceptible to Fas ligand‐mediated apoptosis
Author(s) -
Chen YungYi,
Jeffery Hannah C.,
Hunter Stuart,
Bhogal Ricky,
Birtwistle Jane,
Braitch Manjit Kaur,
Roberts Sheree,
Ming Mikaela,
Hannah Jack,
Thomas Clare,
Adali Gupse,
Hübscher Stefan G.,
Syn WingKin,
Afford Simon,
Lalor Patricia F.,
Adams David H.,
Oo Ye H.
Publication year - 2016
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.28517
Subject(s) - proinflammatory cytokine , immunology , fas ligand , apoptosis , biology , cd8 , effector , cytokine , fas receptor , immune system , cancer research , microbiology and biotechnology , inflammation , programmed cell death , biochemistry
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. (H epatology 2016;64:138–150)