Properties of regulatory B cells regulating B cell targets

Abstract

Regulatory B cells (Bregs) have shown promise as anti‐rejection therapy applied to organ transplantation. However, less is known about their effect on other B cell populations that are involved in chronic graft rejection. We recently uncovered that naïve B cells, stimulated by TLR ligand agonists, converted into B cells with regulatory properties (Bregs‐TLR) that prevented allograft rejection. Here, we examine the granular phenotype and regulatory properties of Breg‐TLR cells suppressing B cells. Cocultures of Bregs‐TLR with LPS‐activated B cells showed a dose‐dependent suppression of targeted B cell proliferation. Adoptive transfers of Bregs‐TLR induced a decline in antibody responses to antigenically disparate skin grafts. The role of Breg BCR specificity in regulation was assessed using B cell‐deficient mice replenished with transgenic BCR (OB1) and TCR (OT‐II) lymphocytes of matching antigenic specificity. Results indicated that proliferation of OB1 B cells, mediated through help from CD4+ OT‐II cells, was suppressed by OB1 Bregs of similar specificity. Transcriptomic analyses indicated that Bregs‐TLR suppression is associated with a block in targeted B cell differentiation controlled by PRDM1 (Blimp1). This work uncovered the regulatory properties of a new brand of Breg cells and provided mechanistic insights into potential applications of Breg therapy in transplantation.

Leveraging the tolerogenic potential of TNF-α and regulatory B cells in organ transplantation

“…The effort to characterize the molecular and biochemical mechanisms by which the regulatory subset of suppressive B cells was not made until the turn of the 21st century when three studies showed that B cells could suppress inflammation through IL-10 production in murine models of colitis, encephalomyelitis (EAE), and arthritis ( 2 , 3 , 14 ). These findings were extended to transplantation models with the observation that B cells were required to develop transplantation tolerance induced by antibody treatments ( 7 , 15 – 17 ). Studies on genetically modified B cells and B cells from IL-10-deficient mice showed that defective Breg differentiation and function causes chronic inflammation ( 14 ).…”

“…Studies on genetically modified B cells and B cells from IL-10-deficient mice showed that defective Breg differentiation and function causes chronic inflammation ( 14 ). Bregs promote immunological tolerance through suppression of T cell expansion, downregulation of the production of pro-inflammatory cytokines, and maintenance of immune homeostasis through the synthesis of immune modulating cytokines TGF-β, IL-35, and IL-10 and by promotion of regulatory T cells (Tregs) ( 7 , 14 , 16 , 18 ).…”

“…Bregs have also been observed to release Tumor Necrosis Factor alpha (TNF-α), a cytokine with both pro- and anti-inflammatory signaling pathways ( 5 , 6 ). This potentially pro-inflammatory cytokine may compromise Breg tolerogenic function via mechanisms potentially similar to those blocking Treg or conventional T cell activation ( 7 , 8 ). TNF-α is thought to engage two distinct receptors on targeted cells, TNFR1 and TNFR2, and activate two opposing signaling pathways.…”

The 2022 FASEB virtual Catalyst Conference on B Cells in Injury and Regeneration, March 30, 2022

“…Interestingly, donor-specific Bregs-TLR are more efficient at promoting graft survival, suggesting that local targeting via the Bcell receptor may play a role in specific homing of the regulatory cells to the graft. 11 A recent study from the same group further showed that Bregs-TLR can inhibit cognate Bcell activation, proliferation, and development into plasma cells. It was hypothesized that because Bregs-TLR express very high levels of major histocompatibility complex class II, they may induce CD4+ T cell anergy by presenting relevant antigens in a tolerogenic milieu.…”

“…The group further focused on characterizing subsets of Breg‐TLR cells through single‐cell RNA sequencing, showing that B cells stimulated through the TLR‐9 and TLR‐4 pathways have a unique expression profile, characterized by high expression of TGFβ. Interestingly, donor‐specific Bregs‐TLR are more efficient at promoting graft survival, suggesting that local targeting via the Bcell receptor may play a role in specific homing of the regulatory cells to the graft 11 . A recent study from the same group further showed that Bregs‐TLR can inhibit cognate Bcell activation, proliferation, and development into plasma cells.…”