Regulatory B cells: Synergistic cellular mechanisms and therapeutic potential for alleviating transplant rejection

Posttransplantation rejection remains a critical challenge in organ transplantation. While immunosuppressants improve graft survival, their long-term side effects compromise patient quality of life, necessitating novel, side effect-free strategies to reduce the incidence of rejection. Regulatory B cells (Bregs), an immunomodulatory B lymphocyte subset within the immune microenvironment, have the potential to mitigate transplant rejection. However, Bregs alone are insufficient to control rejection, and their suppressive effects are notably limited in the absence of immunosuppression, highlighting their dependence on synergistic interactions with other regulatory mechanisms. This review summarizes the diverse phenotypes of Bregs and elucidates their immunomodulatory mechanisms, with a focus on cellular interactions (e.g., with Tregs, macrophages, dendritic cells, and NK cells) and cytokine secretion (e.g., IL-10, TGF-β, and IL-35). We critically evaluate animal and clinical trial data concerning the role of Bregs in transplantation, discussing their potential as therapeutic targets and the current limitations and future directions for harnessing Bregs to alleviate transplant rejection.