Carcinoembryonic antigen-related cell adhesion molecule 1 controls IL-2-dependent regulatory T-cell induction in immune-mediated hepatitis in mice

TY - JOUR

T1 - Carcinoembryonic antigen-related cell adhesion molecule 1 controls IL-2-dependent regulatory T-cell induction in immune-mediated hepatitis in mice

AU - Horst, Andrea Kristina

AU - Wegscheid, Claudia

AU - Schaefers, Christoph

AU - Schiller, Birgit

AU - Neumann, Katrin

AU - Lunemann, Sebastian

AU - Langeneckert, Annika E

AU - Oldhafer, Karl J

AU - Weiler-Normann, Christina

AU - Lang, Karl S

AU - Singer, Bernhard B

AU - Altfeld, Marcus

AU - Diehl, Linda

AU - Tiegs, Gisa

N1 - © 2018 by the American Association for the Study of Liver Diseases.

PY - 2018/7

Y1 - 2018/7

N2 - 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).

AB - 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).

KW - Journal Article

KW - Humans

KW - Mice, Inbred C57BL

KW - Cell Adhesion Molecules/physiology

KW - Interleukin-2/metabolism

KW - STAT5 Transcription Factor/metabolism

KW - T-Lymphocytes, Regulatory/physiology

KW - Antigens, CD/physiology

KW - Male

KW - Concanavalin A

KW - Case-Control Studies

KW - Hepatitis, Autoimmune/immunology

KW - Animals

KW - Female

KW - Primary Cell Culture

U2 - 10.1002/hep.29812

DO - 10.1002/hep.29812

M3 - SCORING: Journal article

C2 - 29377208

VL - 68

SP - 200

EP - 214

JO - HEPATOLOGY

JF - HEPATOLOGY

SN - 0270-9139

IS - 1

ER -