Role of gamma-delta T cells in liver inflammation and fibrosis

Abstract

Conventional adaptive T cell responses contribute to liver inflammation and fibrogenesis, especially in chronic viral infections and autoimmune hepatitis. However, the role of unconventional gamma-delta (γδ) T cells in liver diseases is less clear. In the past two decades, accumulating evidence revealed that γδ T cell numbers remarkably increase in the liver upon various inflammatory conditions in mice and humans. More recent studies demonstrated that the functional effect of γδ T cells on liver disease progression depends on the subsets involved, which can be identified by the expression of distinct T cell receptor chains and of specific cytokines. Fascinatingly, γδ T cells may have protective as well as pathogenic functions in liver diseases. Interferon γ-producing γδ T cells, for example, induce apoptosis in hepatocytes but also in hepatic tumor cells; while interleukin-17-expressing γδ T cells can downregulate pathogenic effector functions of other immune cells and can promote apoptosis of fibrogenic stellate cells. However, the results obtained in human liver disease as well as murine models are not fully conclusive at present, and the effects of γδ T cells on the outcome of liver disease might vary dependent on etiology and stage of disease. Further definitions of the γδ T cell subsets involved in acute and chronic liver inflammation, as well as their effector cytokines might uncover whether interference with γδ T cells could be a useful target for the treatment of liver disease.

Keywords: Cytokines; Gamma/delta T cells; Interleukin-17; Liver cirrhosis; Liver fibrosis.

Figure 1

Role of gamma-delta T cells in liver disease. Upon liver damage several subsets of gamma-delta (γδ) T cells are recruited to the liver, where they can exert different functions on numerous cell types, ultimately resulting in protective or pathogenic effects on the outcome of liver disease. Pathogenic effects include induction of hepatocyte apoptosis by interferon (IFN)γ - and/or tumor necrosis factor (TNF) α-producing γδ T cells, mediated via death receptor signaling (TNF receptors or Fas/CD95). However, the Vδ1⁺ IFNγ-producing subset can also have beneficial functions as they drive tumor cells apoptosis. Other protective functions can be attributed to Vγ4⁺ T cells, which produce interleukin (IL)-17 and IL-10, and can downregulate pathogenic effector functions of other lymphocytes like natural killer T (NKT) cells or cytotoxic T cells, respectively. IL-17⁺ γδ T cells have also been shown to induce Fas-mediated apoptosis of hepatic stellate cells (the main producer of collagen during hepatofibrogenesis), thereby limiting liver fibrosis.