Andrea Kristina Horst1, Claudia Wegscheid1, Christoph Schaefers1, Birgit Schiller1, Katrin Neumann1, Sebastian Lunemann2, Annika E Langeneckert2, Karl J Oldhafer3, Christina Weiler-Normann4,5, Karl S Lang6,7, Bernhard B Singer8, Marcus Altfeld2, Linda Diehl1, Gisa Tiegs1. 1. Institute of Experimental Immunology and Hepatology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 2. Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany. 3. Department of General & Abdominal Surgery, Asklepios Hospital Barmbek, Semmelweis University of Medicine, Asklepios Campus, Hamburg, Germany. 4. Center for Internal Medicine, I. Medical Clinic and Polyclinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 5. Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 6. Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Essen, Germany. 7. Clinic of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Düsseldorf, Germany. 8. Institute of Anatomy, Medical Faculty, University of Duisburg-Essen, Essen, Germany.
Abstract
A dysbalance between effector T cells (Tconv) and regulatory T cells (Tregs) and impaired Treg function can cause autoimmune liver disease. Therefore, it is important to identify molecular mechanisms that control Treg homeostasis. Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1; CD66a) is an immune coreceptor with dichotomous roles in T-cell regulation: its short isoform (CEACAM1S) can activate T cells and induce Tregs, whereas its long isoform (CEACAM1L), containing two intracellular immune receptor tyrosine-based inhibitory motifs, can inhibit activated T-cell function. In the liver, CEACAM1 has antifibrotic effects in models of nonalcoholic steatohepatitis. However, its role in immune-mediated hepatitis is unknown. In the mouse model of concanavalin A-induced CD4+ T-cell-dependent liver injury, liver damage was aggravated and persisted in Ceacam1-/- mice. Concomitantly, we observed hyperexpansion of Tconv, but reduction of interleukin (IL)-2 production and hepatic forkhead box protein P3+ (Foxp3+ )CD4+ Treg numbers. CEACAM1-/- CD4+ T cells showed impaired IL-2-mediated signal transducer and activator of transcription 5 (STAT5) phosphorylation, which correlated with a failure of naïve CEACAM1-/- CD4+ T cells to convert into Tregs in vitro. Furthermore, CEACAM1-/- Tregs expressed reduced levels of Foxp3, CD25, and B-cell lymphoma 2. Adoptive transfer experiments demonstrated that hepatic Treg expansion and suppressive activity required CEACAM1 expression on both CD4+ T cells and Tregs. We identified predominant CEACAM1S expression on hepatic CD4+ T cells and Tregs from mice with acute liver injury and expression of both isoforms in liver-derived CD4+ T-cell clones from patients with liver injury. CONCLUSION: Our data suggest that CEACAM1S expression in CD4+ T cells augments IL-2 production and STAT5 phosphorylation leading to enhanced Treg induction and stability, which, ultimately, confers protection from T-cell-mediated liver injury. (Hepatology 2018;68:200-214).
A dysbalance between effector T cells (Tconv) and regulatory T cells (Tregs) and impaired Treg function can cause autoimmune liver disease. Therefore, it is important to identify molecular mechanisms that control Treg homeostasis. Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1; CD66a) is an immune coreceptor with dichotomous roles in T-cell regulation: its short isoform (CEACAM1S) can activate T cells and induce Tregs, whereas its long isoform (CEACAM1L), containing two intracellular immune receptor tyrosine-based inhibitory motifs, can inhibit activated T-cell function. In the liver, CEACAM1 has antifibrotic effects in models of nonalcoholic steatohepatitis. However, its role in immune-mediated hepatitis is unknown. In the mouse model of concanavalin A-induced CD4+ T-cell-dependent liver injury, liver damage was aggravated and persisted in Ceacam1-/- mice. Concomitantly, we observed hyperexpansion of Tconv, but reduction of interleukin (IL)-2 production and hepatic forkhead box protein P3+ (Foxp3+ )CD4+ Treg numbers. CEACAM1-/- CD4+ T cells showed impaired IL-2-mediated signal transducer and activator of transcription 5 (STAT5) phosphorylation, which correlated with a failure of naïve CEACAM1-/- CD4+ T cells to convert into Tregs in vitro. Furthermore, CEACAM1-/- Tregs expressed reduced levels of Foxp3, CD25, and B-cell lymphoma 2. Adoptive transfer experiments demonstrated that hepatic Treg expansion and suppressive activity required CEACAM1 expression on both CD4+ T cells and Tregs. We identified predominant CEACAM1S expression on hepatic CD4+ T cells and Tregs from mice with acute liver injury and expression of both isoforms in liver-derived CD4+ T-cell clones from patients with liver injury. CONCLUSION: Our data suggest that CEACAM1S expression in CD4+ T cells augments IL-2 production and STAT5 phosphorylation leading to enhanced Treg induction and stability, which, ultimately, confers protection from T-cell-mediated liver injury. (Hepatology 2018;68:200-214).
Authors: Julia Zöller; Jana-Fabienne Ebel; Vishal Khairnar; Verena Schmitt; Robert Klopfleisch; Jana Meiners; Virginia Seiffart; Wiebke Hansen; Jan Buer; Bernhard B Singer; Karl S Lang; Astrid M Westendorf Journal: Gut Microbes Date: 2020-06-10
Authors: Kojiro Nakamura; Shoichi Kageyama; Fady M Kaldas; Hirofumi Hirao; Takahiro Ito; Kentaro Kadono; Kenneth J Dery; Hidenobu Kojima; David W Gjertson; Rebecca A Sosa; Maciej Kujawski; Ronald W Busuttil; Elaine F Reed; Jerzy W Kupiec-Weglinski Journal: J Clin Invest Date: 2020-05-01 Impact factor: 14.808
Authors: Esther Klaile; Mario M Müller; Cristina Zubiría-Barrera; Saskia Brehme; Tilman E Klassert; Magdalena Stock; Adrian Durotin; Tien D Nguyen; Sabina Feer; Bernhard B Singer; Peter F Zipfel; Sven Rudolphi; Ilse D Jacobsen; Hortense Slevogt Journal: Front Microbiol Date: 2019-11-26 Impact factor: 5.640
Authors: Alexander Queck; Annika F Fink; Evelyn Sirait-Fischer; Sabrina Rüschenbaum; Dominique Thomas; Ryan G Snodgrass; Gerd Geisslinger; Hideo A Baba; Jonel Trebicka; Stefan Zeuzem; Andreas Weigert; Christian M Lange; Bernhard Brüne Journal: Front Immunol Date: 2020-07-14 Impact factor: 7.561