In colorectal cancer mast cells contribute to systemic regulatory T-cell dysfunction
- 22 March 2010
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 107 (14), 6430-6435
- https://doi.org/10.1073/pnas.0913683107
Abstract
T-regulatory cells (Treg) and mast cells (MC) are abundant in colorectal cancer (CRC) tumors. Interaction between the two is known to promote immune suppression or loss of Treg functions and autoimmunity. Here, we demonstrate that in both human CRC and murine polyposis the outcome of this interaction is the generation of potently immune suppressive but proinflammatory Treg (DeltaTreg). These Treg shut down IL10, gain potential to express IL17, and switch from suppressing to promoting MC expansion and degranulation. This change is also brought about by direct coculture of MC and Treg, or culture of Treg in medium containing IL6 and IL2. IL6 deficiency in the bone marrow of mice susceptible to polyposis eliminated IL17 production by the polyp infiltrating Treg, but did not significantly affect the growth of polyps or the generation of proinflammatory Treg. IL6-deficient MC could generate proinflammatory Treg. Thus, MC induce Treg to switch function and escalate inflammation in CRC without losing T-cell-suppressive properties. IL6 and IL17 are not needed in this process.Keywords
This publication has 35 references indexed in Scilit:
- Current developments with peptide-based human tumor vaccinesCurrent Opinion in Oncology, 2009
- Intraepithelial Effector (CD3+)/Regulatory (FoxP3+) T-Cell Ratio Predicts a Clinical Outcome of Human Colon CarcinomaGastroenterology, 2009
- Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitisNature Immunology, 2009
- Mast cells counteract regulatory T-cell suppression through interleukin-6 and OX40/OX40L axis toward Th17-cell differentiationBlood, 2009
- Mast Cell Degranulation Breaks Peripheral ToleranceAmerican Journal of Transplantation, 2009
- IL-6 Signaling in Psoriasis Prevents Immune Suppression by Regulatory T CellsPublished by The American Association of Immunologists ,2009
- Mast cells in tumor growth: Angiogenesis, tissue remodelling and immune-modulationBiochimica et Biophysica Acta (BBA) - Reviews on Cancer, 2009
- Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environmentsBlood, 2009
- Endogenous IL-17 contributes to reduced tumor growth and metastasisPublished by American Society of Hematology ,2009
- IL-17 can promote tumor growth through an IL-6–Stat3 signaling pathwayThe Journal of Experimental Medicine, 2009