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J Immunol. 2015 Feb 15;194(4):1602-8. doi: 10.4049/jimmunol.1402632. Epub 2015 Jan 12.

Tim-1 is essential for induction and maintenance of IL-10 in regulatory B cells and their regulation of tissue inflammation.

Author information

1
Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115; sxiao2@rics.bwh.harvard.edu vkuchroo@rics.bwh.harvard.edu.
2
Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
3
Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304; and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305.

Abstract

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.

PMID:
25582854
PMCID:
PMC4346345
DOI:
10.4049/jimmunol.1402632
[Indexed for MEDLINE]
Free PMC Article

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