Naturally Activated Vγ4 γδ T Cells Play a Protective Role in Tumor Immunity through Expression of Eomesodermin

Wang, He; Hao, Jianlei; Dong, Siyuan; Gao, Yunfei; Tao, Jing; Chi, Hongbo; Flavell, Richard A.; O’Brien, Rebecca L.; Born, Willi K.; Craft, Joseph; Han, Jihong; Wang, Puyue; Zhao, Lingyun; Wu, Jun; Yin, Zhinan

doi:10.4049/jimmunol.0903767

Cited by 84 publications

(106 citation statements)

References 38 publications

(45 reference statements)

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“…The role of gd T cells was previously assessed in the widely used B16-F0 or B16-F10 melanoma transplantable models. Some studies highlight a protective role of gd T cells in melanoma, [27][28][29] whereas other reports show that gd T cells promote melanoma progression 30,31 or have any effects on lung foci formation. 32 Transplantable models could provoke an inflammatory environment subsequently modulating tumor-specific immune responses that could explain some of these controversial results.…”

Section: Discussionmentioning

confidence: 99%

Nitric oxide synthase 2 is involved in the pro-tumorigenic potential of γδ17 T cells in melanoma

et al. 2016

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ABSTRACTgd T lymphocytes may exert either protective or tumor-promoting functions in cancer, mostly based on their polarization toward interferon (IFN)-g or interleukin (IL)-17 productions, respectively. Here, we demonstrate that gd T cells accelerate the spontaneous metastatic melanoma development in a model of transgenic mice for the human RET oncogene (Ret mice). We identify unanticipated roles of inducible nitric oxide synthase (NOS2) in favoring the recruitment of pro-tumor gd T cells within the primary tumor. gd T cells isolated from Ret mice deficient for NOS2 produced more IFNg and less IL-17 than their counterparts from Ret mice. By supporting IL-17 production by gd T cells, NOS2 leads to the recruitment of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and metastasis formation. NOS2 also reduces the cytotoxicity of gd T cells toward melanoma cells. Finally, we detected NOS2 expressing gd T cells in the primary tumor and tumor-draining lymph nodes in Ret mice, but also in human melanoma. Overall our results support that this NOS2 autocrine expression is responsible for the polarization of gd T cells toward a pro-tumor profile.

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Section: Discussionmentioning

confidence: 99%

Nitric oxide synthase 2 is involved in the pro-tumorigenic potential of γδ17 T cells in melanoma

et al. 2016

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“…The distinct roles of these two subsets of gd T cells have also been demonstrated in autoimmune disease models and infection immunity (25)(26)(27). Our recent studies have demonstrated a critical role of Vg4 gd T cells in tumor immunity through eomesodermin-controlled, IFN-g-and perforin-dependent mechanisms (28). However, the role of Vg1 gd T cells, especially whether Vg1 gd T cells can directly interact with Vg4 gd T cells in tumor immunity, remains unknown.…”

Section: G D T Cells Have Many Unique Features and Functions (1-6)mentioning

confidence: 93%

Regulatory Role of Vγ1 γδ T Cells in Tumor Immunity through IL-4 Production

Hao

Dong

Xia

et al. 2011

The Journal of Immunology

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It has been demonstrated that the two main subsets of peripheral γδ T cells, Vγ1 and Vγ4, have divergent functions in many diseases models. Recently, we reported that Vγ4 γδ T cells played a protective role in tumor immunity through eomesodermin-controlled mechanisms. However, the precise roles of Vγ1 γδ T cells in tumor immunity, especially whether Vγ1 γδ T cells have any interaction with Vγ4 γδ T cells, remain unknown. We demonstrated in this paper that Vγ1 γδ T cells suppressed Vγ4 γδ T cell-mediated antitumor function both in vitro and in vivo, and this suppression was cell contact independent. Using neutralizing anti–IL-4 Ab or IL-4−/− mice, we determined the suppressive factor derived from Vγ1 γδ T cells was IL-4. Indeed, treatment of Vγ4 γδ T cells with rIL-4 significantly reduced expression levels of NKG2D, perforin, and IFN-γ. Finally, Vγ1 γδ T cells produced more IL-4 and expressed significantly higher level of GATA-3 upon Th2 priming in comparison with Vγ4 γδ T cells. Therefore, to our knowledge, our results established for the first time a negative regulatory role of Vγ1 γδ T cells in Vγ4 γδ T cell-mediated antitumor immunity through cell contact-independent and IL-4–mediated mechanisms. Selective depletion of this suppressive subset of γδ T cells may be beneficial for tumor immune therapy.

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“…Neither cell type expressed Gata3 or Foxp3. However, He et al 52 detected the expression of Foxp3, which suggests that IL-4 may have a pro-inflammatory effect on Vd1 T cells. The molecular basis for the secretion of IFNc by cd T cells, especially Vd2 T cells, is potentially due to a high level of T-bet expression and absence of GATA-3.…”

Section: Il-4-induced Vd1 T-cell Bias Weakened the Overall Immune Resmentioning

confidence: 98%

A new effect of IL-4 on human γδ T cells: promoting regulatory Vδ1 T cells via IL-10 production and inhibiting function of Vδ2 T cells

et al. 2015

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Interleukin 4 (IL-4) has a variety of immune functions, including helper T-cell (Th-cell) differentiation and innate immune-response processes. However, the impact of IL-4 on gamma delta (cd) T cells remains unclear. In this study, we investigate the effects of IL-4 on the activation and proliferation of cd T cells and the balance between variable delta 1 (Vd1) and Vd2 T cells in humans. The results show that IL-4 inhibits the activation of cd T cells in the presence of cd T-cell receptor (TCR) stimulation in a STAT6-dependent manner. IL-4 promoted the growth of activated cd T cells and increased the levels of Vd1 T cells, which in turn inhibited Vd2 T-cell growth via significant IL-10 secretion. Vd1 T cells secreted significantly less interferon gamma (IFNc) and more IL-10 relative to Vd2. Furthermore, Vd1 T cells showed relatively low levels of Natural Killer Group 2D (NKG2D) expression in the presence of IL-4, suggesting that Vd1 T cells weaken the cd T cell-mediated anti-tumor immune response. For the first time, our findings demonstrate a negative regulatory role of IL-4 in cd T cell-mediated anti-tumor immunity. Cellular & Molecular Immunology

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Naturally Activated Vγ4 γδ T Cells Play a Protective Role in Tumor Immunity through Expression of Eomesodermin

Cited by 84 publications

References 38 publications

Nitric oxide synthase 2 is involved in the pro-tumorigenic potential of γδ17 T cells in melanoma

Nitric oxide synthase 2 is involved in the pro-tumorigenic potential of γδ17 T cells in melanoma

Regulatory Role of Vγ1 γδ T Cells in Tumor Immunity through IL-4 Production

A new effect of IL-4 on human γδ T cells: promoting regulatory Vδ1 T cells via IL-10 production and inhibiting function of Vδ2 T cells

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