The current understanding of the phenotypic and functional properties of human regulatory B cells (Bregs)

Abstract

B cells can have a wide range of pro- and anti- inflammatory functions. A subset of B cells called regulatory B cells (Bregs) can potently suppress immune responses. Bregs have been shown to maintain immune homeostasis and modulate inflammatory responses. Bregs are an exciting cellular target across a range of diseases, including Breg induction in autoimmunity, allergy and transplantation, and Breg suppression in cancers and infection. Bregs exhibit a remarkable phenotypic heterogeneity, rendering their unequivocal identification a challenging task. The lack of a universally accepted and exclusive surface marker set for Bregs across various studies contributes to inconsistencies in their categorization. This review paper presents a comprehensive overview of the current understanding of the phenotypic and functional properties of human Bregs while addressing the persisting ambiguities and discrepancies in their characterization. Finally, the paper examines the promising therapeutic opportunities presented by Bregs as their immunomodulatory capacities have gained attention in the context of autoimmune diseases, allergic conditions, and cancer. We explore the exciting potential in harnessing Bregs as potential therapeutic agents and the avenues that remain open for the development of Breg-based treatment strategies.

Keywords: B cells; Bregs; IL-10; IL-25; TGF-B; autoimmune disease; infection; regulation.

Figure 1.

Key mechanisms of Bregs on suppressing other immune cells. (Top) Cell surface receptors expressed by Bregs with known immunosuppressive effects on iNKT and CD4 T cells, and (bottom) secreted factors with known immunosuppressive effects on CD4 and CD8 T cells as well as Tregs. Created in BioRender. Wu, S. (2024) BioRender.com/b10q919.

Figure 2.

Mechanisms of Breg responses in cancer, infection, autoimmune conditions and transplantation. In cancer and infections, an expansion of IL-10⁺ Bregs and TGF-β secreting Bregs mediate the conversion of effector T cells into Tregs and inhibit the activation of other effector T cell populations. In contrast, a reduction or dysfunction of Bregs have been shown in autoimmune conditions and transplantation responses, where IL-10⁺ Bregs inhibit the secretion of proinflammatory cytokines by Th1, Th17, and monocytes. Further, Bregs inhibit expansion of T cells and promote differentiation of Tregs. IL-10⁺ Bregs can hinder the anti-tumour responses of CD4⁺ and CD8⁺ T cells by curbing their generation of inflammatory cytokines. TGF-β+ Bregs can also induce CD4⁺ T cells to become Tregs. TGF-β- and GrB-secreting Bregs inhibit proliferation of CD4⁺ T and CD8⁺ T cells. Bregs express surface molecules including PD-1 which bind to T cells and limit their anti-tumoural responses. Created in BioRender. Wu, S. (2024) BioRender.com/s75v103.

Figure 3.

Opportunities and challenges of Bregs. Bregs could be targeted for depletion to augment anti-tumour immune responses. In vitro expansion of patient-derived Bregs and adoptive transfer into patients could suppress autoimmune or alloimmune responses in patients with autoimmune disorders or transplants. Boosting endogenous Breg populations via therapeutic agents could promote Breg expansion and induce tolerance in these patients. Created in BioRender. Wu, S. (2024) BioRender.com/a43i376.