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Eur J Immunol. 2010 Jul;40(7):1927-37. doi: 10.1002/eji.200940157.

Tumor-infiltrating IL-17-producing gammadelta T cells support the progression of tumor by promoting angiogenesis.

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Division of ROYCE' Health Bioscience, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.


Based on the evidence that IL-17 is a key cytokine involved in various inflammatory diseases, we explored the critical role of IL-17-producing gammadelta T cells for tumor development in tumor-bearing mouse model. IL-17(-/-) mice exhibited a significant reduction of tumor growth, concomitantly with the decrease of vascular density at lesion area, indicating a pro-tumor property of IL-17. Among tumor-infiltrating lymphocytes (TIL), gammadelta T cells were the major cellular source of IL-17. Analysis of TCR repertoires in TIL-gammadelta T cells showed that circulating gammadelta T cells, but not skin resident Vgamma5(+)gammadelta T cells, produced IL-17. Neutralizing antibodies against IL-23, IL-6, and TGF-beta, which were produced within the tumor microenvironment, inhibited the induction of IL-17-producing gammadelta T cells. IL-17 production by tumor-infiltrating gammadelta T cells was blocked by anti-gammadeltaTCR or anti-NKG2D antibodies, indicating that these ligands, expressed within the tumor microenvironment, are involved in gammadelta T-cell activation. The IL-17-producing TIL-gammadelta T cells exhibited reduced levels of perforin mRNA expression, but increased levels of COX-2 mRNA expression. Together, our findings support the novel concept that IL-17-producing gammadelta T cells, generated in response to tumor microenvironment, act as tumor-promoting cells by inducing angiogenesis.

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