Type 1 T Helper Cells Induce the Accumulation of Myeloid-Derived Suppressor Cells in the Inflamed Tgfb1 Knockout Mouse Liver
| Autor: | James D. Gorham, James G. Cripps, Ian Blumenthal, Ann Maria, Jing Wang |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
CD4-Positive T-Lymphocytes
T cell Cell Communication Autoimmune hepatitis Biology Nitric Oxide Article Hepatitis Transforming Growth Factor beta1 Interferon-gamma Mice Interleukin 21 Immune system medicine Animals Cytotoxic T cell Myeloid Cells Myeloid Progenitor Cells Cell Proliferation Mice Knockout CD11b Antigen Hepatology Th1 Cells Natural killer T cell medicine.disease medicine.anatomical_structure Liver Immunology Cancer research Hepatic stellate cell Myeloid-derived Suppressor Cell Receptors Chemokine |
| Zdroj: | Hepatology. 52:1350-1359 |
| ISSN: | 0270-9139 |
| Popis: | T cells are the proximal agents of parenchymal liver damage in inflammatory liver diseases such as autoimmune hepatitis (AIH) and viral hepatitis. In AIH, CD4+ T cells infiltrate liver parenchyma (1) and release hepatotoxic cytokines such as IFN-γ and TNF-α (2, 3). IFN-γ expression by ex vivo cultured T cells strongly correlates with disease activity (4), implicating type 1 T cell responses in hepatocellular damage. In hepatitis C virus (HCV) infection, liver pathology results from the activity of T cells producing IFN-γ within liver parenchyma, since HCV is not cytopathic (5–7). IFN-γ is essential for parenchymal damage in mouse models of T cell mediated liver injury, including Concanavalin A -induced liver injury (8), and spontaneous liver injury in BALB/c TGF-β1 knockout mice (9). A common theme, therefore, in immune mediated liver injury is pathology associated with activated T cells producing IFN-γ. Given the potential for liver damage by activated Th1 cells, it is important to identify mechanisms that regulate their activity. A variety of liver resident cells participate in the regulation of T cells, including Treg, dendritic cells, Kupffer cells, NK cells, NKT cells, stellate cells, and liver sinusoidal epithelial cells (10). Whether regulatory immunocytes accumulate in liver in response to activated T cells is not known. Such cells may represent an important negative feedback mechanism mitigating pathology mediated by T cell activation. It is reasonable to postulate that inflammatory pathology in liver is attributable both to aberrant activation of T cells and to a deficit in appropriate counter-regulatory mechanisms. Studies emerging from the field of tumor immunity show that tumor-associated inflammation induces the development and accumulation of myeloid-lineage cells with immunomodulatory activity. Termed myeloid derived suppressor cells (MDSC), these pleiomorphic cells are capable of suppressing T cell proliferation and subjugating T cell mediated immunity (11, 12). MDSC comprise a heterogenous group of myeloid cells, employing a variety of mechanisms to inhibit T cell responses. Murine MDSC are operationally defined as CD11b+Gr1+ myeloid cells that suppress T cell proliferation (11, 12). While MDSC have been most extensively described in the context of tumors, recent studies show their involvement in inflammatory responses not associated with tumors (13, 14). MDSC home to liver in tumor-bearing mice (15), and hepatocellular carcinoma, like other solid tumors, exhibit associated populations of MDSC (16, 17), but little is otherwise known about MDSC in liver, particularly in inflammatory pathology. Here, we demonstrate in the BALB/c TGF-β1 knockout mouse model that Th1 cells, through release of IFN-γ, drive accumulation in liver of an MDSC population that can effectively inhibit T cell proliferation through a mechanism involving expression of inducible nitric oxide synthase (iNOS) and the production of nitric oxide (NO). |
| Databáze: | OpenAIRE |
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