期刊
IMMUNITY
卷 29, 期 5, 页码 758-770出版社
CELL PRESS
DOI: 10.1016/j.immuni.2008.09.018
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类别
资金
- Juvenile Diabetes Research Foundation [4-2007-1057]
- National Institutes of Health (NIH) [1R01A151530-5]
- Young Chair
- National Institute of Diabetes and Digestive and Kidney Diseases
- Canadian Institutes of Health Research
- Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, NIH
CD4(+)Foxp3(+) regulatory T (Treg) cells originate primarily from thymic differentiation, but conversion of mature T lymphocytes to Foxp3 positivity can be elicited by several means, including in vitro activation in the presence of TGF-beta. Retinoic acid (RA) increases TGF-beta-induced expression of Foxp3, through unknown molecular mechanisms. We showed here that, rather than enhancing TGF-beta signaling directly in naive CD4(+) T cells, RA negatively regulated an accompanying population of CD4(+) T cells with a CD44(hi) memory and effector phenotype. These memory cells actively inhibited the TGF-beta-induced conversion of naive CD4(+) T cells through the synthesis of a set of cytokines (IL-4, IL-21, IFN-gamma) whose expression was coordinately curtailed by RA. This indirect effect was evident in vivo and required the expression of the RA receptor alpha. Thus, cytokine-producing CD44(hi) cells actively restrain TGF-beta-mediated Foxp3 expression in naive T cells, and this balance can be shifted or fine-tuned by RA.
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