ArticleHepatology (Baltimore, Md.)2016
Human intrahepatic regulatory T cells are functional, require IL-2 from effector cells for survival, and are susceptible to Fas ligand-mediated apoptosis.
Article in Hepatology (Baltimore, Md.), 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers, 1 of them a synthesis that pooled it.
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Who cites it
41 citing papers in PubMed, 1 synthesis or guideline pooled it, 83 citations in OpenAlex.
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- Donor liver natural killer cells ameliorate liver allograft rejection via inducing apoptosis of alloreactive CD8Scientific reports · 2025Article
- The dual role of TIGIT in regulatory and effector T cells in chronic liver disease.JHEP reports : innovation in hepatology · 2025Article
- Bridging Immune Evasion and Vascular Dynamics for Novel Therapeutic Frontiers in Hepatocellular Carcinoma.Cancers · 2025Review
- Common pathological mechanisms and therapeutic strategies in primary Sjogren's syndrome and primary biliary cholangitis: from tissue immune microenvironment to targeted therapy.Frontiers in immunology · 2025Review
- Bone Marrow and Peripheral Blood Mononuclear Cell Phenotype Changes after Cultivation and Autologous Infusion in Patients with Primary Biliary Cholangitis.Iranian journal of medical sciences · 2024Article
- Immunosuppressive CD29Gut · 2024Article
- Regulatory T cells in inflamed liver are dysfunctional in murine primary biliary cholangitis.Clinical and experimental immunology · 2024Article
- Autoimmune Hepatitis and Fibrosis.Journal of clinical medicine · 2023Review
- Spatial transcriptomics identifies enriched gene expression and cell types in human liver fibrosis.Hepatology communications · 2022Article
- Challenges and opportunities in achieving effective regulatory T cell therapy in autoimmune liver disease.Seminars in immunopathology · 2022Review
- IL-2 availability regulates the tissue specific phenotype of murine intra-hepatic Tregs.Frontiers in immunology · 2022Article
- Fine-tuning of regulatory T cells is indispensable for the metabolic steatosis-related hepatocellular carcinoma: A review.Frontiers in cell and developmental biology · 2022Review
- Pathogenesis of Autoimmune Hepatitis-Cellular and Molecular Mechanisms.International journal of molecular sciences · 2021Review
- Functional heterogeneity of CD4Seminars in immunopathology · 2021Review
- Exploring the Pathogenic Role and Therapeutic Implications of Interleukin 2 in Autoimmune Hepatitis.Digestive diseases and sciences · 2021Review
- Failure of thymic deletion and instability of autoreactive Tregs drive autoimmunity in immune-privileged liver.JCI insight · 2021Article
- Regulatory T-Cell Therapy in Liver Transplantation and Chronic Liver Disease.Frontiers in immunology · 2021Review
- Antigen presentation, autoantibody production, and therapeutic targets in autoimmune liver disease.Cellular & molecular immunology · 2021Review
Corrections and comments
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Authors and funding
17 authors at 5 institutions in 2 countries.
Funding
Abstract
unlabelledRegulatory T cells (Treg ) suppress T effector cell proliferation and maintain immune homeostasis. Autoimmune liver diseases persist despite high frequencies of Treg in the liver, suggesting that the local hepatic microenvironment might affect Treg stability, survival, and 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 (postendothelial migrated Treg [PEM Treg ]) 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 interleukin (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 PEM Treg phosphorylated STAT5 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 coculture with cholangiocytes or their supernatants induced preferential apoptosis of Treg compared with CD8 effector cells. Treg from diseased livers expressed high levels of CD95, and their apoptosis was inhibited by IL-2 or blockade of CD95.
conclusionRecruitment through endothelium does not impair Treg stability, but a proinflammatory 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 autoimmune liver disease. (Hepatology 2016;64:138-150).
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