Regulatory B cells: the cutting edge of immune tolerance in kidney transplantation

Abstract

Kidney transplantation is the optimal treatment for end-stage renal diseases. Although great improvement has been achieved, immune tolerance is still the Holy Grail that every organ transplant practitioner pursues. The role of B cells in transplantation has long been considered simply to serve as precursors of plasma cells, which produce alloantibodies and induce antibody-mediated rejection. Recent research indicates that a specialized subset of B cells plays an important role in immune regulation, which has been well demonstrated in autoimmune diseases, infections, and cancers. This category of regulatory B cells (Bregs) differs from conventional B cells, and they may help develop a novel immunomodulatory therapeutic strategy to achieve immune tolerance in transplantation. Here, we review the latest evidence regarding phenotypes, functions, and effectors of Bregs and discuss their diverse effects on kidney transplantation.

Regulatory B cells require antigen recognition for effective allograft tolerance induction

“…13,14 Furthermore, CD22 −/− mice lack the CD22-mediated counter-regulation of the BCR, and these animals show an increased number of immature B cells, which may have regulatory functions. 11,15 These studies suggest that BCR signaling increases the number of Bregs and the strength of their suppressive action. Some models of allergic airway disease indicate that adoptive transfer of B cells from animals exposed to a specific allergenic antigen produce allergen-specific protection.…”

“…In the EAE model, CD19‐deficient mice develop a severe, nonremitting form of autoimmunity, suggesting that fully functional BCR signaling is required for adequate B cell–mediated control of autoimmunity . Furthermore, CD22 −/− mice lack the CD22‐mediated counter‐regulation of the BCR, and these animals show an increased number of immature B cells, which may have regulatory functions . These studies suggest that BCR signaling increases the number of Bregs and the strength of their suppressive action.…”

Tissue talks: immunophenotype of cells infiltrating the graft explains histological findings and the benefits of belatacept at 10 years

“…Conversely, circulating naive/transitional T1 B reg cells have been shown to support development of immunotolerance in kidney transplantation function [7,12,13]. Blair and colleagues have defined these latter cells as a B reg cell pool (1-3% of whole splenic B cells), with many subtypes that display a common CD19 + /CD24 hi /CD38 hi phenotype [14,15].…”

B cells in transplant tolerance and rejection: friends or foes?

“…Although a number of subsets have been described as Bregs, the two B‐cell subsets that are best characterized are CD5 + CD19 + CD1d hi B10 and CD19 + CD21 hi CD23 hi CD24 hi transitional‐2 (T2) Breg cells. While no true consensus definition of Bregs has been agreed upon, characterizations generally center around the secretion of IL‐10 . Likewise, no signature set of phenotypic markers for Bregs is analogous to the markers CD25 and FoxP3 that characterize Tregs.…”

“…Candidate phenotypic profiles for Bregs include CD5 + CD1d hi B cells and T‐cell Ig and mucin domain protein 1 (TIM‐1 + ) B cells . Mechanistically, Bregs function through IL‐10 and through secretion of other cytokines (TGF‐β, IL‐35) to suppress CD4+ T‐cell proliferation, suppress CD8+ effector T‐cell function, induce T‐cell apoptosis through binding the FAS and PD‐1 receptors, induce Tregs, suppress antigen‐presenting and cytokine secretion by dendritic cells and M1 macrophages, and suppress natural killer (NK) cells and neutrophils . Evidence for Bregs’ salutary effect is sometimes inferred from experiments involving pan‐B‐cell depletion, which has been shown to accelerate rejection in models of heart and skin allotransplantation and in human clinical heart and kidney transplant trials .…”