title: TIM-1 signaling is required for maintenance and induction of regulatory B cells.
abstract: Apart from their role in humoral immunity, B cells can exhibit IL-10-dependent regulatory activity (Bregs). These regulatory subpopulations have been shown to inhibit inflammation and allograft rejection. However, our understanding of Bregs has been hampered by their rarity, lack of a specific marker, and poor insight into their induction and maintenance. We previously demonstrated that T cell immunoglobulin mucin domain-1 (TIM-1) identifies over 70% of IL-10-producing B cells, irrespective of other markers. We now show that TIM-1 is the primary receptor responsible for Breg induction by apoptotic cells (ACs). However, B cells that express a mutant form of TIM-1 lacking the mucin domain (TIM-1(Δmucin) ) exhibit decreased phosphatidylserine binding and are unable to produce IL-10 in response to ACs or by specific ligation with anti-TIM-1. TIM-1(Δmucin) mice also exhibit accelerated allograft rejection, which appears to be due in part to their defect in both baseline and induced IL-10(+) Bregs, since a single transfer of WT TIM-1(+) B cells can restore long-term graft survival. These data suggest that TIM-1 signaling plays a direct role in Breg maintenance and induction both under physiological conditions (in response to ACs) and in response to therapy through TIM-1 ligation. Moreover, they directly demonstrate that the mucin domain regulates TIM-1 signaling.
authors: Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors: M Y
authors: MY
authors: Yeung
authors: Q
authors: Q
authors: Ding
authors: C R
authors: CR
authors: Brooks
authors: S
authors: S
authors: Xiao
authors: C J
authors: CJ
authors: Workman
authors: D A A
authors: DA
authors: Vignali
authors: T
authors: T
authors: Ueno
authors: R F
authors: RF
authors: Padera
authors: V K
authors: VK
authors: Kuchroo
authors: N
authors: N
authors: Najafian
authors: D M
authors: DM
authors: Rothstein
mesh_terms: D000818:Animals; D060151:B-Lymphocytes, Regulatory / Q000166:cytology*; D006085:Graft Survival; D000072596:Hepatitis A Virus Cellular Receptor 1; D016753:Interleukin-10 / Q000096:biosynthesis; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D015398:Signal Transduction
chemical_list: C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D008565:Membrane Proteins; D016753:Interleukin-10
keywords: Animal models; B cell biology; basic (laboratory) research/science; cell death: apoptosis; immunobiology; tolerance: experimental
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