Vγ4 γδ T Cell-Derived IL-17A Negatively Regulates NKT Cell Function in Con A-Induced Fulminant Hepatitis

Con A-induced fulminant hepatitis is a well-known animal model for acute liver failure. However, the role of gamma delta T cells in this model is undefined. In this report, using TCR delta(-/-) mice, we demonstrated a protective role of gamma delta T cells in Con A-induced hepatitis model. TCR delta(-/-) mice showed significantly decreased levels of IL-17A and IL-17F in the Con A-treated liver tissue, and reconstitution of TCR delta(-/-) mice with wild-type ( Wt), but not IL-17A(-/-), gd T cells significantly reduced hepatitis, strongly suggesting a critical role of IL-17A in mediating the protective effect of gamma delta T cells. Interestingly, only V gamma 4, but not V gamma 1, gamma delta T cells exerted such a protective effect. Furthermore, depletion of NKT cells in TCR delta(-/-) mice completely abolished hepatitis, and NKT cells from Con A-challenged liver tissues of TCR delta(-/-) mice expressed significantly higher amounts of proinflammatory cytokine IFN-gamma than those from Wt mice, indicating that gamma delta T cells protected hepatitis through targeting NKT cells. Finally, abnormal capacity of IFN-gamma production by NKT cells of TCR delta(-/-) mice could only be downregulated by transferring Wt, but not IL-17(-/-), V gamma 4 gamma delta T cells, confirming an essential role of V gamma 4-derived IL-17A in regulating the function of NKT cells. In summary, our report thus demonstrated a novel function of V gamma 4 gamma delta T cells in mediating a protective effect against Con A-induced fulminant hepatitis through negatively regulating function of NKT cells in an IL-17A-dependent manner, and transferring V gamma 4 gamma delta T cells may provide a novel therapeutic approach for this devastating liver disease. The Journal of Immunology, 2011, 187: 5007-5014.