IFNγ and CTLA-4 Drive Hepatic CD4 T-Cell Tolerance and Protection From Autoimmunity in MiceSummary
Background & Aims: The liver has a distinct capacity to induce immune tolerance to hepatic antigens. Although liver tolerance can be advantageous for preventing autoimmune and inflammatory diseases, it also can be detrimental by preventing immune surveillance of infected or malignant cells....
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X23001686 |
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| author | Daria Krzikalla Alena Laschtowitz Lisa Leypoldt Cornelia Gottwick Pia Averhoff Sören Weidemann Ansgar W. Lohse Samuel Huber Christoph Schramm Dorothee Schwinge Johannes Herkel Antonella Carambia |
| author_facet | Daria Krzikalla Alena Laschtowitz Lisa Leypoldt Cornelia Gottwick Pia Averhoff Sören Weidemann Ansgar W. Lohse Samuel Huber Christoph Schramm Dorothee Schwinge Johannes Herkel Antonella Carambia |
| author_sort | Daria Krzikalla |
| collection | DOAJ |
| description | Background & Aims: The liver has a distinct capacity to induce immune tolerance to hepatic antigens. Although liver tolerance can be advantageous for preventing autoimmune and inflammatory diseases, it also can be detrimental by preventing immune surveillance of infected or malignant cells. Here, we investigated the immune mechanisms that establish hepatic tolerance. Methods: Tolerance was investigated in C-reactive protein (CRP)–myelin basic protein (MBP) mice expressing the neuroantigen MBP in hepatocytes, providing profound resistance to MBP-induced neuroinflammation. Tolerance induction was studied after transfer of MBP-specific CD4 T cells into CRP–MBP mice, and tolerance mechanisms were tested using depleting or blocking antibodies. Results: Although tolerant CRP–MBP mice display increased numbers of forkhead box P3+ regulatory T cells, we here found them not essential for the maintenance of hepatic tolerance. Instead, upon MBP recognition in the liver, MBP-specific T cells became activated to produce interferon (IFN)γ, which, in turn, induced local up-regulation of recruitment molecules, including Chemokine (C-X-C motif) ligand9 and its receptor C-X-C motif chemokine receptor3, facilitating endothelial translocation and redirection of MBP-specific T cells into the hepatic parenchyma. There, the translocated MBP-specific CD4 T cells partly converted into interleukin 10–producing type 1 regulatory T cells, and significantly up-regulated the expression of immune checkpoint molecules, notably cytotoxic T-lymphocyte–associated protein 4 (CTLA-4). Intriguingly, although liver tolerance was not affected by impairment of interleukin 10 signaling, concomitant blockade of IFNγ and CTLA-4 abrogated hepatic tolerance induction to MBP, resulting in neuroinflammatory autoimmune disease in these mice. Conclusions: IFNγ-mediated redirection of autoreactive CD4 T cells into the liver and up-regulation of checkpoint molecules, including CTLA-4, were essential for tolerance induction in the liver, hence representing a potential treatment target for boosting or preventing liver tolerance. |
| first_indexed | 2024-03-11T11:10:31Z |
| format | Article |
| id | doaj.art-5bdb57d96fae45dab3880fcdea472873 |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-03-11T11:10:31Z |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-5bdb57d96fae45dab3880fcdea4728732023-11-12T04:40:13ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2024-01-011717991IFNγ and CTLA-4 Drive Hepatic CD4 T-Cell Tolerance and Protection From Autoimmunity in MiceSummaryDaria Krzikalla0Alena Laschtowitz1Lisa Leypoldt2Cornelia Gottwick3Pia Averhoff4Sören Weidemann5Ansgar W. Lohse6Samuel Huber7Christoph Schramm8Dorothee Schwinge9Johannes Herkel10Antonella Carambia11Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Correspondence Address correspondence to: Johannes Herkel, PhD, or Antonella Carambia, PhD, Department of Medicine I, University Medical Centre Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Correspondence Address correspondence to: Johannes Herkel, PhD, or Antonella Carambia, PhD, Department of Medicine I, University Medical Centre Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.Background & Aims: The liver has a distinct capacity to induce immune tolerance to hepatic antigens. Although liver tolerance can be advantageous for preventing autoimmune and inflammatory diseases, it also can be detrimental by preventing immune surveillance of infected or malignant cells. Here, we investigated the immune mechanisms that establish hepatic tolerance. Methods: Tolerance was investigated in C-reactive protein (CRP)–myelin basic protein (MBP) mice expressing the neuroantigen MBP in hepatocytes, providing profound resistance to MBP-induced neuroinflammation. Tolerance induction was studied after transfer of MBP-specific CD4 T cells into CRP–MBP mice, and tolerance mechanisms were tested using depleting or blocking antibodies. Results: Although tolerant CRP–MBP mice display increased numbers of forkhead box P3+ regulatory T cells, we here found them not essential for the maintenance of hepatic tolerance. Instead, upon MBP recognition in the liver, MBP-specific T cells became activated to produce interferon (IFN)γ, which, in turn, induced local up-regulation of recruitment molecules, including Chemokine (C-X-C motif) ligand9 and its receptor C-X-C motif chemokine receptor3, facilitating endothelial translocation and redirection of MBP-specific T cells into the hepatic parenchyma. There, the translocated MBP-specific CD4 T cells partly converted into interleukin 10–producing type 1 regulatory T cells, and significantly up-regulated the expression of immune checkpoint molecules, notably cytotoxic T-lymphocyte–associated protein 4 (CTLA-4). Intriguingly, although liver tolerance was not affected by impairment of interleukin 10 signaling, concomitant blockade of IFNγ and CTLA-4 abrogated hepatic tolerance induction to MBP, resulting in neuroinflammatory autoimmune disease in these mice. Conclusions: IFNγ-mediated redirection of autoreactive CD4 T cells into the liver and up-regulation of checkpoint molecules, including CTLA-4, were essential for tolerance induction in the liver, hence representing a potential treatment target for boosting or preventing liver tolerance.http://www.sciencedirect.com/science/article/pii/S2352345X23001686Hepatic ToleranceRegulatory T CellsImmune CheckpointsCo-inhibition |
| spellingShingle | Daria Krzikalla Alena Laschtowitz Lisa Leypoldt Cornelia Gottwick Pia Averhoff Sören Weidemann Ansgar W. Lohse Samuel Huber Christoph Schramm Dorothee Schwinge Johannes Herkel Antonella Carambia IFNγ and CTLA-4 Drive Hepatic CD4 T-Cell Tolerance and Protection From Autoimmunity in MiceSummary Cellular and Molecular Gastroenterology and Hepatology Hepatic Tolerance Regulatory T Cells Immune Checkpoints Co-inhibition |
| title | IFNγ and CTLA-4 Drive Hepatic CD4 T-Cell Tolerance and Protection From Autoimmunity in MiceSummary |
| title_full | IFNγ and CTLA-4 Drive Hepatic CD4 T-Cell Tolerance and Protection From Autoimmunity in MiceSummary |
| title_fullStr | IFNγ and CTLA-4 Drive Hepatic CD4 T-Cell Tolerance and Protection From Autoimmunity in MiceSummary |
| title_full_unstemmed | IFNγ and CTLA-4 Drive Hepatic CD4 T-Cell Tolerance and Protection From Autoimmunity in MiceSummary |
| title_short | IFNγ and CTLA-4 Drive Hepatic CD4 T-Cell Tolerance and Protection From Autoimmunity in MiceSummary |
| title_sort | ifnγ and ctla 4 drive hepatic cd4 t cell tolerance and protection from autoimmunity in micesummary |
| topic | Hepatic Tolerance Regulatory T Cells Immune Checkpoints Co-inhibition |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X23001686 |
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