期刊
GASTROENTEROLOGY
卷 141, 期 6, 页码 2109-2118出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2011.09.015
关键词
Immune Regulation; Autoimmunity; Allergy; Intestine; Peyer's Patch
资金
- EMBO
- Crohn's & Colitis Foundation of America
- National Institutes of Health [R00 AI075285-02, AI435801, NS38037, P30 AR042689, DP2 2009A054301]
- National Multiple Sclerosis Society [RG4111A1]
- Boston Area Diabetes Endocrinology Research Center
- Cancer Research Institute
- Massachusetts Life Science Center
BACKGROUND & AIMS: Induction of oral immune tolerance (OT) blocks proinflammatory responses to orally administered antigens and might be used to treat autoimmune conditions. We investigated whether gut-tropic T cells that express the integrin alpha 4 beta 7 and the chemokine receptor CCR9 are required for OT. METHODS: Skin delayed-type hypersensitivity and experimental autoimmune encephalomyelitis were used to monitor OT in mice. To assess the role of receptors that mediate localization of lymphocytes to the gut (gut-homing receptors) in induction of OT, we studied CCR9(-/-) and beta 7(-/-) mice and also blocked the alpha 4 beta 7 ligand MAdCAM-1 in wild-type mice. We used DEREG and Scurfy mice to assess the role of Foxp3(+) regulatory T cells (Treg) and IL-10(-/-) and IL-10R beta(-/-) mice to examine the role of interleukin (IL)-10 in induction of OT. RESULTS: OT could not be induced in CCR9(-/-) or beta 7(-/-) mice, or when MAdCAM-1 was blocked in wild-type mice, indicating that gut-homing receptors are required for oral tolerization. Consistent with the role of all-trans retinoic acid in inducing gut-homing T cells, OT could not be induced in mice depleted of vitamin A. OT was rescued in CCR9(-/-) mice following adoptive transfer of wild-type T cells, but not CCR9(-/-) or beta 7(-/-) T cells. Gut-homing T cells are therefore necessary and sufficient to induce OT. Wild-type Treg and IL-10 were required to restore OT to CCR9-/- mice, indicating that homing and functional differentiation of IL-10-producing Treg in the gut is required for OT. Conversely, transfer of CCR9(-/-) or beta 7(-/-) T cells to wild-type mice partially inhibited OT. CONCLUSIONS: Expression of CCR9 and alpha 4 beta 7 on T cells and their subsequent localization to the gut is required for induction of OT in mice. Therapies designed to block gut-homing receptors might, under some conditions, interfere with normal tolerogenic mechanisms in the intestinal mucosa.
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