title: Regulatory B cells are identified by expression of TIM-1 and can be induced through TIM-1 ligation to promote tolerance in mice.
abstract: T cell Ig domain and mucin domain protein 1 (TIM-1) is a costimulatory molecule that regulates immune responses by modulating CD4+ T cell effector differentiation. However, the function of TIM-1 on other immune cell populations is unknown. Here, we show that in vivo in mice, TIM-1 is predominantly expressed on B rather than T cells. Importantly, TIM-1 was expressed by a large majority of IL-10-expressing regulatory B cells in all major B cell subpopulations, including transitional, marginal zone, and follicular B cells, as well as the B cell population characterized as CD1d(hi)CD5+. A low-affinity TIM-1-specific antibody that normally promotes tolerance in mice, actually accelerated (T cell-mediated) immune responsiveness in the absence of B cells. TIM-1+ B cells were highly enriched for IL-4 and IL-10 expression, promoted Th2 responses, and could directly transfer allograft tolerance. Both cytokine expression and number of TIM-1+ regulatory B cells (Bregs) were induced by TIM-1-specific antibody, and this was dependent on IL-4 signaling. Thus, TIM-1 is an inclusive marker for IL-10+ Bregs that can be induced by TIM-1 ligation. These findings suggest that TIM-1 may be a novel therapeutic target for modulating the immune response and provide insight into the signals involved in the generation and induction of Bregs.
authors.affiliation: Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Ding
authors.forename: Melissa
authors.initials: M
authors.lastname: Yeung
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Camirand
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zeng
authors.forename: Hisaya
authors.initials: H
authors.lastname: Akiba
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Geetha
authors.initials: G
authors.lastname: Chalasani
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
authors.forename: Nader
authors.initials: N
authors.lastname: Najafian
authors.forename: David M
authors.initials: DM
authors.lastname: Rothstein
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D000072596:Hepatitis A Virus Cellular Receptor 1; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology; D016131:Lymphocyte Subsets / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D023001:Transplantation Tolerance / Q000276:immunology
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D004268:DNA-Binding Proteins; C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D008565:Membrane Proteins; C499308:Rag2 protein, mouse; D016753:Interleukin-10; D015847:Interleukin-4