title: Tim-1 is essential for induction and maintenance of IL-10 in regulatory B cells and their regulation of tissue inflammation.
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.
authors.affiliation: 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.
authors.forename: Sheng
authors.initials: S
authors.lastname: Xiao
authors.affiliation: Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors.forename: Craig R
authors.initials: CR
authors.lastname: Brooks
authors.affiliation: Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304; and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Sobel
authors.affiliation: 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.
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
mesh_terms: D000818:Animals; D060151:B-Lymphocytes, Regulatory / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D005434:Flow Cytometry; D000072596:Hepatitis A Virus Cellular Receptor 1; D007249:Inflammation / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D060888:Real-Time Polymerase Chain Reaction; D017634:Self Tolerance / Q000276:immunology
chemical_list: C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; C556062:IL10 protein, mouse; D008565:Membrane Proteins; D016753:Interleukin-10