Suppression of allograft rejection by regulatory B cells induced via TLR signaling

JCI Insight. 2022 Sep 8;7(17):e152213. doi: 10.1172/jci.insight.152213.

Abstract

B lymphocytes have long been recognized for their critical contributions to adaptive immunity, providing defense against pathogens through cognate antigen presentation to T cells and Ab production. More recently appreciated is that B cells are also integral in securing self-tolerance; this has led to interest in their therapeutic application to downregulate unwanted immune responses, such as transplant rejection. In this study, we found that PMA- and ionomycin-activated mouse B cells acquire regulatory properties following stimulation through TLR4/TLR9 receptors (Bregs-TLR). Bregs-TLR efficiently inhibited T cell proliferation in vitro and prevented allograft rejection. Unlike most reported Breg activities, the inhibition of alloimmune responses by Bregs-TLR relied on the expression of TGF-β and not IL-10. In vivo, Bregs-TLR interrupted donor-specific T cell expansion and induced Tregs in a TGF-β-dependent manner. RNA-Seq analyses corroborated the involvement of TGF-β pathways in Breg-TLR function, identified potential gene pathways implicated in preventing graft rejection, and suggested targets to foster Breg regulation.

Keywords: Cellular immune response; Immunology; Immunotherapy; Tolerance; Transplantation.

MeSH terms

  • Allografts
  • Animals
  • B-Lymphocytes, Regulatory* / metabolism
  • Lymphocyte Activation
  • Mice
  • Signal Transduction
  • Toll-Like Receptor 4 / metabolism
  • Transforming Growth Factor beta / metabolism

Substances

  • Toll-Like Receptor 4
  • Transforming Growth Factor beta