Regulatory B cells (Bregs) represent a small population of B cells which participates in immunomodulations and in suppression of immune responses. These cells regulate the immune system by different mechanisms. The main mechanism is a production of anti-inflammatory cytokine interleukin 10 (IL-10). The regulatory effects of Bregs were described in various models of inflammation, autoimmune diseases, transplantation reactions and in anti-tumor immunity.
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History
In the 1970s it was noticed that Bregs could suppress immune reaction independently of antibody production. In 1996 Janeway´s group observed an immunomodulation of experimental autoimmune encephalomyelitis (EAE) by B cells. Similar results were shown in a model of chronic colitis one year later. Then a role of Bregs was found in many mouse models of autoimmune diseases as rheumatoid arthritis or systemic lupus erythematosus (SLE).
Development and Breg populations
Bregs can develop from different subsets of B cells. Whether Breg cells uniquely derive from a specific progenitor or originate within conventional B cell subsets is still an open question. Bregs shared many markers with various B cells subsets due to their origin. Mouse Bregs were mainly CD5 and CD1d positive in model of EAE or after exposition of Leishmania major. By contrast mouse Bregs in model of collagen-induced arthritis (CIA) were mainly CD21 and CD23 positive. Breg were found in human, too. Markers of peripheral blood Bregs were molecules CD24 and CD38. However, peripheral blood Bregs were mostly CD24 and CD27 positive after cultivation with anti-CD40 antibody and CpG bacterial DNA. They were also positive for CD25, CD71 and PD-L1 after stimulation by CpG bacterial DNA and through TLR9.
Mechanisms of Breg action
There are several mechanisms of Breg action. Nevertheless, the most examined mechanism is production of IL-10. IL-10 has strong anti-inflammatory effects. and it inhibits or suppresses inflammatory reactions mediated by T cells, especially Th1 type immune reactions. This was shown for example in model EAE, CIA or contact hypersensitivity. Likewise, regulatory B cell subsets have also been demonstrated to inhibit Th1 responses through IL-10 production during chronic infectious diseases such as visceral leishmaniasis. Next suppressive Breg mechanism is production of transforming growth factor (TGF-β), another anti-inflammatory cytokine. Role of Bregs producing TGF-β was found in mouse of SLE or diabetes. Another mechanism of Breg acting involves surface molecules, for example FasL or PD-L1, which cause death of target cells.