doi:10.1016/j.it.2007.10.004 
Copyright © 2007 Elsevier Ltd All rights reserved.
Review
The ‘short’ history of regulatory B cells
Claudia Mauria, 
and Michael R. Ehrensteina
aDepartment of Medicine, University College London, 46 Cleveland Street, London W1T 4JF, UK
Available online 3 December 2007.
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The maintenance of tolerance is the sine qua non of a sophisticated regulatory apparatus to prevent or dampen overzealous immune responses. In addition to the ability of B cells to prime and activate the immune system, B cells with regulatory function (Bregs) have been identified in experimental models of autoimmunity, infections, and cancer, supporting the notion that, similar to regulatory T cells (Tregs), Breg-mediated suppression is an important means for the maintenance of peripheral tolerance. This regulatory function appears to be directly mediated by the production of IL-10 and/or TGFβ and by the ability of B cells to interact with pathogenic T cells to inhibit harmful immune responses. The identification of their existence is of great relevance to the understanding of autoimmune diseases and to the development of new therapeutic strategies.
Figure 1. Demonstration of the existence of T2-MZP Bregs (transitional 2 marginal zone precursor regulatory B cells). Splenocytes were isolated from DBA/1 strain mice during the remission phase of collagen-induced arthritis (CIA) and were enriched for resting B cells by removal of CD43+ cells. B cells were then sorted into T2-MZP (Bregs), MZ (marginal zone B cells), and FO (follicular B cells). Sorted T2-MZP, MZ, and FO B cells were transferred intravenously to syngeneic DBA/1 mice on the same day as experimental induction of arthritis, and the ensuing disease incidence and severity were monitored. The T2-MZP B-cell population is the only one that appears to protect mice from arthritis.
Figure 2. Possible path of T2-MZP regulatory B-cell differentiation in the peripheral immune system. Transitional 2 (T2) B cells differentiate according to microenvironmental stimuli into marginal zone (MZ), follicular (FO) [64], or marginal zone precursor (T2-MZP) regulatory B cells (Bregs). Bregs are unique in requiring simultaneous engagement of B-cell receptors (BCR) by autoantigen and CD40 as costimulatory molecules, which interact with CD154 (CD40L) expressed on autoreactive T cells. Upon CD40 ligation, Bregs acquire the ability to release Interleukin-10 (IL-10) [54]. Whether T2-MZP Bregs also produce TGFβ and protective antibodies is yet to be determined. We cannot currently exclude the possibility that T2-MZP Bregs constitute a different lineage, and, although they are phenotypically indistinguishable from ‘conventional’ T2, functionally they might differ through their release of IL-10.
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Figure 3. Suppressive regulatory B-cell-mediated effector mechanisms in the immune response. Regulatory B cells (Bregs) suppress activation and differentiation of CD4+, CD8+, and NK T cells primarily via the release of the anti-inflammatory cytokines IL-10 and TGFβ. Engagement of costimulatory pathways including CD154-CD40 and CD28-B7 are required for the release of IL-10 by Bregs. A Breg-T cell dialogue results in an inhibition of T-cell activation and Th1 differentiation; induction of Tregs (Tr1); inhibition of DC activation, and hence suppression of T-cell activation; and clearance of apoptotic cells mediated via the release of autoreactive antibodies. The suppressive effect that Bregs exert on T cells might also provoke immune responses against autologous tumor cells. ACAID, anterior chamber-associated immune deviation; CIA, collagen-induced arthritis; EAE, experimental autoimmune encephalomyelitis; IBD, inflammatory bowel disease; NOD, non-obese diabetic (mice); Tr1, Type 1 regulatory cell.
Table 1.
Different Bregs distinguished by their surface markers and putative function
Different studies have reported several potential markers identifying regulatory B cells. However, the majority of these markers, except for CD1d, CD40, and B7, have not been found to be involved in the mechanisms underlying suppression. Whether all of these markers are simultaneously expressed on the same population of regulatory B cells remains to be determined.
a Not all of the markers listed are present on the same cell.
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