Original Article
TIM-1 Signaling Is Required for Maintenance and Induction of Regulatory B Cells

https://doi.org/10.1111/ajt.13087Get rights and content
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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-1Δmucin) exhibit decreased phosphatidylserine binding and are unable to produce IL-10 in response to ACs or by specific ligation with anti-TIM-1. TIM-1Δmucin 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.

Animal models
basic (laboratory) research/science
B cell biology
cell death: apoptosis
immunobiology
tolerance: experimental

Abbreviations

AC
apoptotic cell
BCR
B cell receptor
Breg
regulatory B cell
DC
dendritic cell
EAE
experimental autoimmune encephalitis
IL-4
interleukin-4
IL-10
interleukin-10
IL-35
interleukin-35
KIM-1
kidney injury molecule-1
MZ
marginal zone
PC
phosphatidylcholine
PS
phosphatidylserine
TIM-1
T cell immunoglobulin mucin domain-1
TLR
Toll-like receptor
WT
wild-type

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