TIM-1 signaling is required for maintenance and induction of regulatory B cells.

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. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Citation

M Y Yeung, Q Ding, C R Brooks, S Xiao, C J Workman, D A A Vignali, T Ueno, R F Padera, V K Kuchroo, N Najafian, D M Rothstein. TIM-1 signaling is required for maintenance and induction of regulatory B cells. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2015 Apr;15(4):942-53

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PMID: 25645598

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