title: Vγ4 γδ T cell-derived IL-17A negatively regulates NKT cell function in Con A-induced fulminant hepatitis.
abstract: Con A-induced fulminant hepatitis is a well-known animal model for acute liver failure. However, the role of γδ T cells in this model is undefined. In this report, using TCR δ(-/-) mice, we demonstrated a protective role of γδ T cells in Con A-induced hepatitis model. TCR δ(-/-) mice showed significantly decreased levels of IL-17A and IL-17F in the Con A-treated liver tissue, and reconstitution of TCR δ(-/-) mice with wild-type (Wt), but not IL-17A(-/-), γδ T cells significantly reduced hepatitis, strongly suggesting a critical role of IL-17A in mediating the protective effect of γδ T cells. Interestingly, only Vγ4, but not Vγ1, γδ T cells exerted such a protective effect. Furthermore, depletion of NKT cells in TCR δ(-/-) mice completely abolished hepatitis, and NKT cells from Con A-challenged liver tissues of TCR δ(-/-) mice expressed significantly higher amounts of proinflammatory cytokine IFN-γ than those from Wt mice, indicating that γδ T cells protected hepatitis through targeting NKT cells. Finally, abnormal capacity of IFN-γ production by NKT cells of TCR δ(-/-) mice could only be downregulated by transferring Wt, but not IL-17(-/-), Vγ4 γδ T cells, confirming an essential role of Vγ4-derived IL-17A in regulating the function of NKT cells. In summary, our report thus demonstrated a novel function of Vγ4 γδ 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 Vγ4 γδ T cells may provide a novel therapeutic approach for this devastating liver disease.
authors: State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China.
authors: Na
authors: N
authors: Zhao
authors: Jianlei
authors: J
authors: Hao
authors: Yuanyuan
authors: Y
authors: Ni
authors: Wei
authors: W
authors: Luo
authors: Ruifang
authors: R
authors: Liang
authors: Guangchao
authors: G
authors: Cao
authors: Yapu
authors: Y
authors: Zhao
authors: Puyue
authors: P
authors: Wang
authors: Liqing
authors: L
authors: Zhao
authors: Zhigang
authors: Z
authors: Tian
authors: Richard
authors: R
authors: Flavell
authors: Zhangyong
authors: Z
authors: Hong
authors: Jihong
authors: J
authors: Han
authors: Zhi
authors: Z
authors: Yao
authors: Zhenzhou
authors: Z
authors: Wu
authors: Zhinan
authors: Z
authors: Yin
mesh_terms: D000818:Animals; D003208:Concanavalin A / Q000037:antagonists & inhibitors / Q000633:toxicity*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D005260:Female; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D020381:Interleukin-17 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017114:Liver Failure, Acute / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000096:biosynthesis* / Q000145:classification / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D020381:Interleukin-17; D016692:Receptors, Antigen, T-Cell, gamma-delta; D003208:Concanavalin A; D007371:Interferon-gamma