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

Zhao, Ning; Hao, Jianlei; Ni, Yuanyuan; Luo, Wei; Liang, Ruiying; Cao, Guangchao; Zhao, Yapu; Wang, Puyue; Zhao, Lingyun; Tian, Zhigang; Flavell, Richard A.; Hong, Zhangyong; Han, Jihong; Yao, Zhi; Wu, Zhenzhou; Yin, Zhinan

doi:10.4049/jimmunol.1101315

Cited by 60 publications

(57 citation statements)

References 45 publications

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“…We further identified Vg4 gd T cells as the main subset of gd T cells that produced IL-17A within tumors. Vg4 gd T cell-derived IL-17A has been shown to negatively regulate NKT cell function in Con A-induced fulminant hepatitis (35). To our knowledge, this was the first report demonstrating that Vg4 gd T cells played promoting role in hepatocellular carcinoma through IL-17A production.…”

Section: Discussionmentioning

confidence: 63%

IL-17A Produced by γδ T Cells Promotes Tumor Growth in Hepatocellular Carcinoma

et al. 2014

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Interleukin (IL)-17A is expressed in the tumor microenvironment where it appears to contribute to tumor development, but its precise role in tumor immunity remains controversial. Here, we report mouse genetic evidence that IL-17A is critical for tumor growth. IL-17A-deficient mice exhibited reduced tumor growth, whereas systemic administration of recombinant mouse IL-17A promoted the growth of hepatocellular carcinoma. The tumor-promoting effect of IL-17A was mediated through suppression of antitumor responses, especially CD8 þ Tcell responses. Furthermore, we found that IL-17A was produced mainly by Vg4 gd T cells, insofar as depleting Vg4 gd T cells reduced tumor growth, whereas adoptive transfer of Vg4 gd T cells promoted tumor growth. Mechanistic investigations showed that IL-17A induced CXCL5 production by tumor cells to enhance the infiltration of myeloid-derived suppressor cells (MDSC) to tumor sites in a CXCL5/CXCR2-dependent manner. IL-17A also promoted the suppressive activity of MDSC to reinforce suppression of tumoral immunity. Moreover, we found that MDSC could induce IL-17A-producing gd T cells via production of IL-1b and IL-23. Conversely, IL-17A could also enhance production of IL-1b and IL-23 in MDSC as a positive feedback. Together, our results revealed a novel mechanism involving cross-talk among gd T cells, MDSCs, and tumor cells through IL-17A production. These findings offer new insights into how IL-17A influences tumor immunity, with potential implications for the development of tumor immunotherapy. Cancer Res; 74(7); 1969-82. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 63%

IL-17A Produced by γδ T Cells Promotes Tumor Growth in Hepatocellular Carcinoma

et al. 2014

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“…gdT cells exhibit both regulatory and proinflammatory function (11,12) and are considered important in maintaining OVA-induced oral tolerance, as established oral tolerance could be blocked by depleting gdT cells (13,14). gdT cells were also reported to sustain intestinal mucosa homeostasis during colitis induced by dextran sodium sulfate and 2,4,6-trinitrobenzene sulfonic acid (15,16).…”

Section: Cd11bmentioning

confidence: 99%

γδT Cells Drive Myeloid-Derived Suppressor Cell–Mediated CD8+ T Cell Exhaustion in Hepatitis B Virus–Induced Immunotolerance

Kong

Sun

Chen

et al. 2014

The Journal of Immunology

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The mechanisms of liver hepatitis B virus (HBV)–induced systemic immune tolerance are still elusive, and the role of γδT cells has not yet been described. We examined the function of γδT cells in HBV-carrier mice––immunocompetent mice with plasmid-mediated persistent HBV expression in the liver. In this study, we found that γδT cell deficiency led to a break in HBV-induced tolerance and subsequent recovery of hepatic HBV-specific CD8+ T cells. Of interest, IL-17−/− mice phenocopied TCRδ−/− mice in terms of losing HBV persistence, and adoptive transfer of γδT cells restored HBV-persistent expression in TCRδ−/− mice. We further observed that hepatic CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs) play a major role in this mechanism, as they were significantly reduced in both HBV-carrier TCRδ−/− and IL-17−/− mice. MDSC numbers also recovered after adoptive transfer of γδT cells, particularly Vγ4+ T cells. Furthermore, anti-Gr1–mediated MDSC depletion in HBV-carrier mice accelerated HBV elimination from the host, whereas MDSCs transferred to γδT cell-deficient mice restored HBV-induced tolerance. Accordingly, inhibition of MDSCs by the arginase-1 inhibitor norNOHA enhanced the number of HBV-specific CD8+ T cells and promoted HBV clearance. We also observed enhanced CD8+ T cell number with a notable decline of MDSCs in TCRδ−/− mice compared with wild-type mice during the recombinant adeno-associated virus/HBV1.3 virus infection. Importantly, HBV-carrier TCRδ−/− mice not only exhibited increased anti-HBV CD8+ T cells but also markedly reduced MDSCs. Overall, the current study reveals that γδT cells play a previously unrecognized regulatory role in liver tolerance by mobilizing MDSC infiltration to the liver, leading to MDSC-mediated CD8+ T cell exhaustion.

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“…Liver mononuclear cells were prepared as previously described (29 f/f mice, and 5 3 10 4 cells were resuspended in RPMI 1640 and seeded onto the upper chambers of 24-well transwell plate (5 mm; Costar). Complete medium with 100 ng/ml CXCL-10 (PeproTech) was added into the bottom chambers.…”

Section: Transwell Migrationmentioning

confidence: 99%

Critical Role of Dendritic Cell–Derived IL-27 in Antitumor Immunity through Regulating the Recruitment and Activation of NK and NKT Cells

Wei

Xia

Sun

et al. 2013

The Journal of Immunology

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Critical roles of IL-27 in autoimmune diseases and infections have been reported; however, the contribution of endogenous IL-27 to tumor progression remains elusive. In this study, by using IL-27p28 conditional knockout mice, we demonstrate that IL-27 is critical in protective immune response against methyl-cholanthrene–induced fibrosarcoma and transplanted B16 melanoma, and dendritic cells (DCs) are the primary source. DC-derived IL-27 is required for shaping tumor microenvironment by inducing CXCL-10 expression in myeloid-derived suppressor cells and regulating IL-12 production from DCs, which lead to the recruitment and activation of NK and NKT cells resulting in immunological control of tumors. Indeed, reconstitution of IL-27 or CXCL-10 in tumor site significantly inhibits tumor growth and restores the number and activation of NK and NKT cells. In summary, our study identifies a previous unknown critical role of DC-derived IL-27 in NK and NKT cell–dependent antitumor immunity through shaping tumor microenvironment, and sheds light on developing novel therapeutic approaches based on IL-27.

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

Cited by 60 publications

References 45 publications

IL-17A Produced by γδ T Cells Promotes Tumor Growth in Hepatocellular Carcinoma

IL-17A Produced by γδ T Cells Promotes Tumor Growth in Hepatocellular Carcinoma

γδT Cells Drive Myeloid-Derived Suppressor Cell–Mediated CD8+ T Cell Exhaustion in Hepatitis B Virus–Induced Immunotolerance

Critical Role of Dendritic Cell–Derived IL-27 in Antitumor Immunity through Regulating the Recruitment and Activation of NK and NKT Cells

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