期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 4, 期 164, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.3004566
关键词
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资金
- Northwestern University Interdepartmental ImmunoBiology Flow Cytometry Core Facility
- Eisenberg Foundation
- Northwestern University Flow Cytometry Facility
- Cancer Center Support Grant (National Cancer Institute) [CA060553]
- NIH [1R01CA160436-01, AI089954, AI091962, K08AI080836-01 01]
- Zell Family Award
- Robert H. Lurie Comprehensive Cancer Center
- Pew Scholarship
- Cancer Research Institute Investigator Award
- American Society of Transplantation Basic Science Fellowship Award
The role of regulatory T cells (T-regs) in human colon cancer (CC) remains controversial: high densities of tumor-infiltrating T-regs can correlate with better or worse clinical outcomes depending on the study. In mouse models of cancer, T-regs have been reported to suppress inflammation and protect the host, suppress T cells and protect the tumor, or even have direct cancer-promoting attributes. These different effects may result from the presence of different T-reg subsets. We report the preferential expansion of a T-reg subset in human CC with potent T cell-suppressive, but compromised anti-inflammatory, properties; these cells are distinguished from T-regs present in healthy donors by their coexpression of Foxp3 and ROR gamma t. T-regs with similar attributes were found to be expanded in mouse models of hereditary polyposis. Indeed, ablation of the ROR gamma t gene in Foxp3(+) cells in polyp-prone mice stabilized T-reg anti-inflammatory functions, suppressed inflammation, improved polyp-specific immune surveillance, and severely attenuated polyposis. Ablation of interleukin-6 (IL-6), IL-23, IL-17, or tumor necrosis factor-alpha in polyp-prone mice reduced polyp number but not to the same extent as loss of ROR gamma t. Surprisingly, loss of IL-17A had a dual effect: IL-17A-deficient mice had fewer polyps but continued to have ROR gamma t(+) T-regs and developed invasive cancer. Thus, we conclude that ROR gamma t has a central role in determining the balance between protective and pathogenic T-regs in CC and that T-reg subtype regulates inflammation, potency of immune surveillance, and severity of disease outcome.
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