Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 40, Issue 7, Pages 1927-1937Publisher
WILEY
DOI: 10.1002/eji.200940157
Keywords
gamma delta T cell; IL-17; Tumor microenvironment
Categories
Funding
- Ministry of Education, Culture, Sports, Science and Technology
- Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT)
- JSPS
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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 gamma delta 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), gamma delta T cells were the major cellular source of IL-17. Analysis of TCR repertoires in TIL-gamma delta T cells showed that circulating gamma delta T cells, but not skin resident V gamma 5(+) gamma delta 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 gamma delta T cells. IL-17 production by tumor-infiltrating gamma delta T cells was blocked by anti-gamma delta TCR or anti-NKG2D antibodies, indicating that these ligands, expressed within the tumor microenvironment, are involved in gamma delta T-cell activation. The IL-17-producing TIL-gamma delta 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 gamma delta T cells, generated in response to tumor microenvironment, act as tumor-promoting cells by inducing angiogenesis.
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