Regulatory B cells (Bregs) have been shown to play a critical role in immune homeostasis and in autoimmunity models. We have recently demonstrated that combined anti-TIM-1 and anti-CD45RB antibody treatment generates regulatory B cells necessary for long-term mouse islet allograft survival in a full MHC-mismatch donor-recipient pair. Here we provide evidence that the induction of tolerance by regulatory B cells requires regulatory T cells, specifically: adoptive transfer of Bregs results in an increase in absolute number of Tregs in grafted recipients and depletion of Tregs abrogates transplant tolerance conferred by adoptive transfer of regulatory B cells. We hypothesize that Bregs induce the expansion of Tregs, and demonstrate that Bregs from transplanted but not naive mice express TGF-beta complexed to latency-associated peptide (LAP). Furthermore, Bregs but not naive B cells induce Foxp3 expression in CD4+CD25- T cells by adoptive transfer in vivo and Breg mediated graft prolongation is abrogated by neutralization of TGF-beta activity.

Collectively, these findings suggest that in this model antibody induced Bregs promote tolerance by inducing Tregs, possibly via TGF-beta production.

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