Immunosuppressive Mechanisms of Regulatory B Cells

Abstract

Regulatory B cells (Bregs) is a term that encompasses all B cells that act to suppress immune responses. Bregs contribute to the maintenance of tolerance, limiting ongoing immune responses and reestablishing immune homeostasis. The important role of Bregs in restraining the pathology associated with exacerbated inflammatory responses in autoimmunity and graft rejection has been consistently demonstrated, while more recent studies have suggested a role for this population in other immune-related conditions, such as infections, allergy, cancer, and chronic metabolic diseases. Initial studies identified IL-10 as the hallmark of Breg function; nevertheless, the past decade has seen the discovery of other molecules utilized by human and murine B cells to regulate immune responses. This new arsenal includes other anti-inflammatory cytokines such IL-35 and TGF-β, as well as cell surface proteins like CD1d and PD-L1. In this review, we examine the main suppressive mechanisms employed by these novel Breg populations. We also discuss recent evidence that helps to unravel previously unknown aspects of the phenotype, development, activation, and function of IL-10-producing Bregs, incorporating an overview on those questions that remain obscure.

Keywords: CD1d; IL-10; IL-35; PD-L1; TGF-β; TIM-1; granzyme B; regulatory B cells.

Figure 1

Suppressive mechanisms of Bregs by soluble molecules. (A) IL-10⁺ Bregs inhibit Th1, Th17, and CD8⁺ T cell responses; convert naïve CD4⁺ T cells into regulatory T cell populations; and modulate pro-inflammatory innate cells through the production of IL-10. (B) Likewise, TGF-β⁺ Bregs operate on naïve CD4⁺ T cells to generate FoxP3⁺ Tregs, in addition to induce anergy in CD4⁺ and CD8⁺ T cells. (C) IL-35⁺ Bregs can promote “infectious tolerance” by inducing IL-35-producing Tregs and expanding the generation of IL-35⁺ Bregs. (D) GrB⁺ B cells have been shown to inhibit Th1 and Th17 cell responses and to reduce CD4⁺ T cell proliferation by degrading the TCR ζ-chain. DC, Conventional dendritic cell; GrB, Granzyme B; MΦ, Macrophage; NK, Natural killer cell; NO, Nitric oxide; pDC, Plasmacytoid dendritic cell; TolDC, Tolerogenic dendritic cell; Tr1, Type-1 regulatory T cell.

Figure 2

Different Breg populations utilize cell surface-expressed molecules to suppress immune responses. Bregs interact with NKT cells via CD1d, inducing the production of IFN-γ, which inhibits Th1 and Th17 responses in a murine arthritis model. PD-L1⁺ Bregs decrease the production of pro-inflammatory cytokines by PD-1-expressing CD4⁺ T cells and macrophages and the cytotoxic functions of PD-1-expressing CD8⁺ T cells and NK cells. In addition, they interact with PD-1-expressing follicular helper T cells, leading to an inhibition of humoral immune responses. On the other hand, PD-L1 expressed on tumor cells engage PD-1⁺ Bregs, triggering the production of IL-10 and the suppression of anti-tumor responses. Finally, FasL⁺ B cells induce apoptosis on Fas-expressing CD4⁺ and CD8⁺ T cells, as well as on B cells. GrB, Granzyme B; iTCR, invariant T cell receptor; MΦ, Macrophage; NK, Natural killer cell; NKT, Natural killer T cell; Tfh, Follicular helper T cell.

Figure 3

Model of suppression of immune responses by TIM-1⁺ Bregs. TIM-1⁺ Bregs secrete IL-10 and TGF-β upon engagement of TIM-1 by phosphatidylserine and possibly by interacting with TIM-4-expressing antigen-presenting cells, inhibiting Th1, Th17, and CD8⁺ T cells, as well as inducing regulatory T cell populations. These changes could also be mediated indirectly, by decreasing antigen presentation and the production of pro-inflammatory cytokines by dendritic cells (DCs) or modulating monocytes to differentiate into tolerogenic DCs. DC, Conventional dendritic cell; Mo, Monocyte; TolDC, Tolerogenic dendritic cell; Tr1, Type-1 regulatory T cell.