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Regulatory B cells (Bregs)

Alistair McIntosh, School of Bioscience, University of Birmingham, UK

B cells provide innate immunity

B lymphocytes (or B cells) are white blood cells that are produced in the bone marrow of mammals. Traditionally, B cells were thought to predominantly play a role in positively regulating the immune system by antigen presentation to CD4+, but not CD8+, T cells, which in turn feedback to activate B cells, conferring humoral immunity. The interaction between B cell and T helper cell is important, as demonstrated by B-cell deficient or depleted mice having a decreased immune response upon challenge with a pathogen.

Although the positive regulatory role of B has been established for many years, it is now recognised that certain B-cell lineages can play a role in negatively regulating immune responses, such as reducing inflammation in autoimmune conditions. When B cells are depleted in animal models, there is an increased manifestation of autoimmune disease, suggesting certain B-cell lineages regulate inflammation. These B-cell lineages are referred to as regulatory B cells (Bregs). Various phenotypic variants of cells that appear to negatively regulate immune responses have been identified, with all the variants sharing the ability to produce IL-10, which is not secreted by other B cell subsets. IL-10 is a cytokine that inhibits production of pro-inflammatory cytokines, such as IL-2, IL-3, IFN-γ and TNF-α, and inhibits responses from T-helper type 1 cells (Th1), suggesting that this cytokine functions as the primary molecule by which Bregs elicit a response. A unique CD1dhiCD5+CD19hisubset, identified in spleens of naïve wild-type mice, is suggested as the Breg lineage that contributes to the majority of B cell IL-10 production, once activated by stimulation in vitro. Due to the fact that this novel B-cell subset only produces IL-10, they have been named B10 cells.

Function of regulatory B cells

Unlike T cells, which respond to antigen following cleavage of peptides, B cells can respond directly to naïve antigen, due to the presence of the B-cell receptor (BCR). This suggests an earlier involvement of Bregs in an immune response, when compared to regulatory T cells. However, as a result, the Breg response is also shorter lived than the regulatory T-cell response.

In humans, Bregs represent a very low proportion of the B-cell population (≈0.5% in healthy individuals). However there is substantial proof that Bregs are very important B-cell subsets. Treatment of many autoimmune conditions by B-cell depletion has shown disappointing results. This could be due to depletion of Bregs, in addition to normal B-cells, removing the protective anti-inflammatory effects provided by the Bregs and counterbalancing the positive effects from B-cell depletion. When B cells are depleted in mice, autoimmune diseases can spontaneously develop, providing support for this theory of Breg depletion. As stated above, these protective properties are derived from production of IL-10. It is believed that IL-10 production is activated upon stimulation of Toll-like receptors (TLRs) in mice, or CD40 and TLRs, in the case of Humans. The result following activation is the inhibition of cell subsets that are involved in inflammatory responses, such as T cells or dendritic cells. Bregs can also trigger change in T-cell behaviour via interaction with T-helper cells. Due to their ability to interact with a vast array of other immune subsets, and inhibit pro-inflammatory signals, Bregs could be used as a novel therapeutic in autoimmune diseases.

B cells - regulatory - Figure 1

Figure 1. Suggested interactions between B10 cells and other immune cells. IL-10 regulates activation of various immune cell-subsets including dendritic cells (DC), macrophages, plasma cells (PC), T-helper cells (Th) and B-cells.

Regulatory B-cell lineage

In spite of the evidence for the role of Bregs in the literature, there are still many questions over the origin of Bregs; IL-10-competent B cells seem to respond to stimulus from the BCR. A reduction in the number of IL-10 competent B cells is seen in mice when CD19, a strong positive regulator of BCR signalling, is knocked out. Furthermore, preliminary results suggest that both CD40 and lipopolysaccharide (LPS) stimulation promote production of IL-10 competent B cells. Collectively this suggests that stimulation, mainly in the form of BCR stimulation, is required for IL-10 competence in B cells. Consequently, the question arises whether Bregs are found as a unique subset, or are produced from B cells exposed to correct stimuli. In various studies with mouse models, where B cells with a regulatory role are identified, a unique, consistent phenotype is not observed between the studies. IL-10-producing B cells have been identified in humans; however variable results with regards to the identity of the B cell subset responsible for the IL-10 production are also seen, as with the mouse models. The overall consequence is that the origin, and the overall role, of Bregs in humans still remains unclear.

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