Tim-1 Is Essential for Induction and Maintenance of IL-10 in Regulatory B Cells and Their Regulation of Tissue Inflammation

被引:109
作者
Xiao, Sheng [1 ,2 ]
Brooks, Craig R. [3 ]
Sobel, Raymond A. [4 ,5 ]
Kuchroo, Vijay K. [1 ,2 ]
机构
[1] Harvard Univ, Sch Med, Evergrande Ctr Immunol Dis, Boston, MA 02115 USA
[2] Brigham & Womens Hosp, Boston, MA 02115 USA
[3] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Renal, Boston, MA 02115 USA
[4] Vet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA 94304 USA
[5] Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA
基金
美国国家卫生研究院;
关键词
APOPTOTIC CELLS; PHOSPHATIDYLSERINE RECEPTOR; TH17; CELLS; T-CELLS; MICE; AUTOIMMUNITY; EXPRESSION; ROLES; EFFECTOR; BALANCE;
D O I
10.4049/jimmunol.1402632
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
T cell Ig and mucin domain (Tim)-1 identifies IL-10-producing regulatory B cells (Bregs). Mice on the C57BL/6 background harboring a loss-of-function Tim-1 mutant showed progressive loss of IL-10 production in B cells and with age developed severe multiorgan tissue inflammation. We demonstrate that Tim-1 expression and signaling in Bregs are required for optimal production of IL-10. B cells with Tim-1 defects have impaired IL-10 production but increased proinflammatory cytokine production, including IL-1 and IL-6. Tim-1-deficient B cells promote Th1 and Th17 responses but inhibit the generation of regulatory T cells (Foxp3(+) and IL-10-producing type 1 regulatory T cells) and enhance the severity of experimental autoimmune encephalomyelitis. Mechanistically, Tim-1 on Bregs is required for apoptotic cell (AC) binding to Bregs and for AC-induced IL-10 production in Bregs. Treatment with ACs reduces the severity of experimental autoimmune encephalomyelitis in hosts with wild-type but not Tim-1-deficient Bregs. Collectively, these findings suggest that in addition to serving as a marker for identifying IL-10-producing Bregs, Tim-1 is also critical for maintaining self-tolerance by regulating IL-10 production in Bregs.
引用
收藏
页码:1602 / 1608
页数:7
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