Liver sinusoidal endothelial cells regulate the balance between hepatic immunosuppression and immunosurveillance
As a metabolic center, the liver prevents inappropriate immune responses to abundant dietary antigens within the liver that could result in liver injury. This self-preservation mechanism can however decrease the efficiency of immunosurveillance of malignant cells by CD8 T cells. Hepatocellular carci...
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| Format: | Article |
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1497788/full |
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| author | Kimberly N. Kremer Hadeel A. Khammash Anjelica M. Miranda Lauren N. Rutt Shannon M. Twardy Paige E. Anton Margaret L. Campbell Christian Garza-Ortiz David J. Orlicky Roberta Pelanda Rebecca L. McCullough Raul M. Torres |
| author_facet | Kimberly N. Kremer Hadeel A. Khammash Anjelica M. Miranda Lauren N. Rutt Shannon M. Twardy Paige E. Anton Margaret L. Campbell Christian Garza-Ortiz David J. Orlicky Roberta Pelanda Rebecca L. McCullough Raul M. Torres |
| author_sort | Kimberly N. Kremer |
| collection | DOAJ |
| description | As a metabolic center, the liver prevents inappropriate immune responses to abundant dietary antigens within the liver that could result in liver injury. This self-preservation mechanism can however decrease the efficiency of immunosurveillance of malignant cells by CD8 T cells. Hepatocellular carcinoma (HCC) is initiated by chronic viral infections, chronic alcohol consumption, and/or a fatty diet that leads to liver injury, fibrosis, and cirrhosis. HCC patients have high levels of dysfunctional and exhausted T cells, however, it is unclear which stage of HCC development contributes to T cell dysfunction. Repair of liver injury is initiated by interactions between injured hepatocytes and liver sinusoidal endothelial cells (LSEC), however, chronic injury can lead to fibrosis. Here, using a diethylnitrosamine/carbon tetrachloride (DEN/CCl4) mouse model of early HCC development, we demonstrate that chronic liver injury and fibrosis are sufficient to induce a CD8 T cell exhaustion signature with a corresponding increase in expression of immunosuppressive molecules on LSEC. We show that LSEC alter T cell function at various stages of T cell differentiation/activation. LSEC compete with dendritic cells presenting the same antigen to naïve CD8 T cells resulting in a unique T cell phenotype. Furthermore, LSEC abrogate killing of target cells, in an antigen-dependent manner, by previously activated effector CD8 T cells, and LSEC change the effector cell cytokine profile. Moreover, LSEC induce functional T cell exhaustion under low dose chronic stimulation conditions. Thus, LSEC critically regulate the balance between preventing/limiting liver injury and permitting sufficient tumor immunosurveillance with normal hepatic functions likely contributing to HCC development under conditions of chronic liver insult. |
| format | Article |
| id | doaj-art-d53f4b50ec2f4c3cba67b4b0499c8bc5 |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-d53f4b50ec2f4c3cba67b4b0499c8bc52025-01-17T06:50:47ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-01-011510.3389/fimmu.2024.14977881497788Liver sinusoidal endothelial cells regulate the balance between hepatic immunosuppression and immunosurveillanceKimberly N. Kremer0Hadeel A. Khammash1Anjelica M. Miranda2Lauren N. Rutt3Shannon M. Twardy4Paige E. Anton5Margaret L. Campbell6Christian Garza-Ortiz7David J. Orlicky8Roberta Pelanda9Rebecca L. McCullough10Raul M. Torres11Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United StatesDepartment of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United StatesDepartment of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United StatesDepartment of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, United StatesDepartment of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, United StatesDepartment of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, United StatesDepartment of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United StatesDepartment of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United StatesDepartment of Pathology, University of Colorado School of Medicine, Aurora, CO, United StatesDepartment of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United StatesDepartment of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, United StatesDepartment of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United StatesAs a metabolic center, the liver prevents inappropriate immune responses to abundant dietary antigens within the liver that could result in liver injury. This self-preservation mechanism can however decrease the efficiency of immunosurveillance of malignant cells by CD8 T cells. Hepatocellular carcinoma (HCC) is initiated by chronic viral infections, chronic alcohol consumption, and/or a fatty diet that leads to liver injury, fibrosis, and cirrhosis. HCC patients have high levels of dysfunctional and exhausted T cells, however, it is unclear which stage of HCC development contributes to T cell dysfunction. Repair of liver injury is initiated by interactions between injured hepatocytes and liver sinusoidal endothelial cells (LSEC), however, chronic injury can lead to fibrosis. Here, using a diethylnitrosamine/carbon tetrachloride (DEN/CCl4) mouse model of early HCC development, we demonstrate that chronic liver injury and fibrosis are sufficient to induce a CD8 T cell exhaustion signature with a corresponding increase in expression of immunosuppressive molecules on LSEC. We show that LSEC alter T cell function at various stages of T cell differentiation/activation. LSEC compete with dendritic cells presenting the same antigen to naïve CD8 T cells resulting in a unique T cell phenotype. Furthermore, LSEC abrogate killing of target cells, in an antigen-dependent manner, by previously activated effector CD8 T cells, and LSEC change the effector cell cytokine profile. Moreover, LSEC induce functional T cell exhaustion under low dose chronic stimulation conditions. Thus, LSEC critically regulate the balance between preventing/limiting liver injury and permitting sufficient tumor immunosurveillance with normal hepatic functions likely contributing to HCC development under conditions of chronic liver insult.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1497788/fullliver sinusoidal endothelial cellsT cell exhaustionhepatocellular carcinomaT cellImmunosuppression |
| spellingShingle | Kimberly N. Kremer Hadeel A. Khammash Anjelica M. Miranda Lauren N. Rutt Shannon M. Twardy Paige E. Anton Margaret L. Campbell Christian Garza-Ortiz David J. Orlicky Roberta Pelanda Rebecca L. McCullough Raul M. Torres Liver sinusoidal endothelial cells regulate the balance between hepatic immunosuppression and immunosurveillance Frontiers in Immunology liver sinusoidal endothelial cells T cell exhaustion hepatocellular carcinoma T cell Immunosuppression |
| title | Liver sinusoidal endothelial cells regulate the balance between hepatic immunosuppression and immunosurveillance |
| title_full | Liver sinusoidal endothelial cells regulate the balance between hepatic immunosuppression and immunosurveillance |
| title_fullStr | Liver sinusoidal endothelial cells regulate the balance between hepatic immunosuppression and immunosurveillance |
| title_full_unstemmed | Liver sinusoidal endothelial cells regulate the balance between hepatic immunosuppression and immunosurveillance |
| title_short | Liver sinusoidal endothelial cells regulate the balance between hepatic immunosuppression and immunosurveillance |
| title_sort | liver sinusoidal endothelial cells regulate the balance between hepatic immunosuppression and immunosurveillance |
| topic | liver sinusoidal endothelial cells T cell exhaustion hepatocellular carcinoma T cell Immunosuppression |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1497788/full |
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