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Regulatory T-cell conditioning endows activated effector T cells with suppressor function in autoimmune hepatitis/autoimmune sclerosing cholangitis.

ABSTRACT: Imbalance between T regulatory (Treg) and T effector (Teff) cells is likely to contribute to the induction and perpetuation of liver damage in autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (AISC) either through inability of Tregs to restrain proliferation and effector cytokine production by responders or through conversion of Tregs into T helper type 1 (Th1) or type 17 (Th17) effector lymphocytes. We investigated the effect of Treg skewing on the phenotypic and functional properties of CD4+ CD127+ CD25high cells, an activated subset of Teff, in 32 patients with AIH and 20 with AISC and in 36 healthy subjects. In AIH/AISC we noted a substantial increase in peripheral blood-derived CD4+ CD127+ CD25high cells that display a Th1/Th17 phenotypic profile, as reflected by heightened interferon gamma and interleukin 17 (IL-17) production as well as by high levels of T-bet and related orphan receptor 3 expression, which is strongly correlated with disease activity. CD4+ CD127+ CD25high cells are unresponsive to low-dose IL-2 and in patients have marked proliferative ability, further enhanced by stimulation with IL-7. CD4+ CD127+ CD25high cells obtained from CD4+ cells exposed to Treg polarizing conditions display enhanced IL-10 production; up-regulate CD49b and LAG-3, markers of T regulatory 1 cells; and effectively suppress responder cell proliferation in both healthy subjects and AIH/AISC patients through a mechanism which is dependent on interferon gamma and IL-17. The suppressive function of CD4+ CD127+ CD25high cells is maintained upon proinflammatory challenge in healthy subjects but not in AIH/AISC. CONCLUSION:Treg skewing confers activated Teff phenotypic and functional properties of T regulatory 1 cells in health and in AIH/AISC, though suppressive function is lost in patients upon proinflammatory challenge; protracted modulation of the inflammatory environment is required to attenuate the effector potential while boosting immunoregulatory properties in Teff. (Hepatology 2017;66:1570-1584).

SUBMITTER: Liberal R

PROVIDER: S-EPMC5689077 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Regulatory T-cell conditioning endows activated effector T cells with suppressor function in autoimmune hepatitis/autoimmune sclerosing cholangitis.

Liberal Rodrigo R Grant Charlotte R CR Yuksel Muhammed M Graham Jonathon J Kalbasi Alireza A Ma Yun Y Heneghan Michael A MA Mieli-Vergani Giorgina G Vergani Diego D Longhi Maria Serena MS

Hepatology (Baltimore, Md.) 20171003 5

Imbalance between T regulatory (Treg) and T effector (Teff) cells is likely to contribute to the induction and perpetuation of liver damage in autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (AISC) either through inability of Tregs to restrain proliferation and effector cytokine production by responders or through conversion of Tregs into T helper type 1 (Th1) or type 17 (Th17) effector lymphocytes. We investigated the effect of Treg skewing on the phenotypic and functional prop ...[more]

PMID: 28597951

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Project description:BackgroundA previously healthy 22-year-old woman presented with abdominal pain and jaundice. She had a reagent antinuclear factor (1:640, with a homogeneous nuclear pattern) and hypergammaglobulinemia (2.16 g/dL). Anti-smooth muscle, anti-mitochondrial and anti-liver-kidney microsomal antibody type 1 antibodies were negative. Magnetic resonance cholangiography showed a cirrhotic liver with multiple focal areas of strictures of the intrahepatic bile ducts, with associated dilations. Liver biopsy demonstrated periportal necroinflammatory activity, plasmocyte infiltration and advanced fibrosis. Colonoscopy showed ulcerative pancolitis and mild activity (Mayo score 1), with a spared rectum. Treatment with corticosteroids, azathioprine, ursodeoxycholic acid and mesalamine was initiated, with improvement in laboratory tests. The patient was referred for a liver transplantation evaluation.AimTo report the case of a female patient with autoimmune hepatitis and primary sclerosing cholangitis (PSC) overlap syndrome associated with ulcerative colitis and to systematically review the available cases of autoimmune hepatitis and PSC overlap syndrome.MethodsIn accordance with preferred reporting items for systematic reviews and meta-analysis protocols guidelines, retrieval of studies was based on medical subject headings and health sciences descriptors, which were combined using Boolean operators. Searches were run on the electronic databases Scopus, Web of Science, MEDLINE (PubMed), Biblioteca Regional de Medicina, Latin American and Caribbean Health Sciences Literature, Cochrane Library for Systematic Reviews and Opengray.eu. Languages were restricted to English, Spanish and Portuguese. There was no date of publication restrictions. The reference lists of the studies retrieved were searched manually.ResultsThe search strategy retrieved 3349 references. In the final analysis, 44 references were included, with a total of 109 cases reported. The most common clinical finding was jaundice and 43.5% of cases were associated with inflammatory bowel disease. Of these, 27.6% were cases of Crohn's disease, 68% of ulcerative colitis, and 6.4% of indeterminate colitis. Most patients were treated with steroids. All-cause mortality was 3.7%.ConclusionPSC and autoimmune hepatitis overlap syndrome is generally associated with inflammatory bowel disease and has low mortality and good response to treatment.

Project description:Background & aimsIn autoimmune hepatitis (AIH), the imbalance between regulatory T cells (Tregs) and T-helper type 17 (Th17) cells has been linked to low levels of CD39, an ectoenzyme that hydrolyses ATP, ultimately generating immunosuppressive adenosine. Upregulation of CD39 results from activation of aryl hydrocarbon receptor (AHR), which mediates toxin responses to modulate T-cell immunity. In this study, we investigated whether altered AHR signalling underlies defective CD39 expression and function in AIH Tregs and Th17 cells, therefore contributing to regulatory/effector cell imbalance.MethodsTregs and Th17 cells, obtained from the peripheral blood of 49 patients with AIH and 21 healthy individuals (HI), were tested for response to endogenous and exogenous AHR ligands.ResultsWhen compared to those of HI, AIH-derived Tregs and Th17 cells displayed impaired responses to AHR activation, reflected by impaired upregulation of CD39, delayed increase in ectoenzymatic activity, and defective Treg suppressive function. These impairments resulted, at least in part, from heightened levels of AHRR and Erα in Tregs and high HIF-1α in Th17 cells, and were reverted upon molecular blockade. Importantly, in AIH-derived Tregs, the binding affinity of AHR was higher for Erα than ARNT.ConclusionsIn AIH, high levels of AHRR and HIF-1α inhibit AHR signalling in Tregs and Th17 cells. AHR non-canonical binding to Erα further amplifies the lack of effective CD39 upregulation. Blockade of these inhibitory and/or non-canonical activation pathways represents a potential therapeutic approach to restore CD39 and immunohomeostasis in AIH.Lay summaryIn patients with autoimmune hepatitis, the imbalance between regulatory T cells and T helper type-17 cells is linked to dysfunction of the aryl hydrocarbon receptor pathway, resulting from aberrant inhibition or non-canonical activation. These alterations impair Treg- and Th17 cell-induced upregulation of CD39, an ectoenzyme key to immunoregulation. Blockade of excessive inhibition or non-canonical activation of the aryl hydrocarbon receptor pathway might represent a novel therapeutic strategy to control inflammation while restoring immune balance in autoimmune hepatitis.

Dataset Information

Regulatory T-cell conditioning endows activated effector T cells with suppressor function in autoimmune hepatitis/autoimmune sclerosing cholangitis.

Publications

Regulatory T-cell conditioning endows activated effector T cells with suppressor function in autoimmune hepatitis/autoimmune sclerosing cholangitis.

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