Regulatory B cell

Source: Wikipedia, the free encyclopedia.

Regulatory B cells (Bregs or Breg cells) represent a small population of

autoimmune diseases, transplantation reactions, and in anti-tumor immunity.[1][2][3]

History

In the 1970s it was noticed that Bregs could suppress immune reaction independently of

systemic lupus erythematosus (SLE).[8]

Development and populations

Bregs can develop from different subsets of B cells such as immature and mature B cells or

CD71 and PD-L1 after stimulation by CpG bacterial DNA and through TLR9.[17]

Breg subsets identified in human or mice
Subset Species Phenotype Function
B10 cells human, mouse CD24hiCD27+ (human), CD5+CD1dhi (mouse) production of IL-10, suppression of effector CD4+ T cells, monocytes, and DCs[1][2]
Plasmablasts
 human, mouse CD19+CD24hiCD27int (human), CD138+CD44hi (mouse) production of IL10 and TGF-β, suppression of DCs and effector CD4+ T cells [1][2][3]
Plasma cells mouse CD138+MHC-11loB220+ production of IL-10 and IL-35, suppression of NK cells, neutrophils, and effector CD4+ T cells [1][2][3]
Marginal zone B cells
 human, mouse CD19+CD21hiCD23− production of IL-10, induction of Treg cells, suppression of effector CD4+ and CD8+ T cells[1][2][3][11]
Br1 cells human CD19+CD25hiCD71hi CD73− production of IL-10, suppress inflammatory responses, induction of
IgG4 production[1]
GrB+B cells human CD19+CD38+CD1d+IgM+CD147+ production of granzyme B, degradation of T cell receptor, inhibition of CD4+ T cell proliferation and Th1 and Th17 responses [1][3]
CD9+ B cells human, mouse CD19+CD9+ production of IL-10, suppression of Th2 and Th17 inflammation[1]
CD5+CD1d+ cells human CD19+CD5+CD1dhi production of IL-10, suppression of Th17 response[1]
B1a cells mouse CD19+CD5+ production of IL-10, suppression of TLR-mediated inflammation[1]
Killer B cells mouse CD19+CD5+FasL+ induction of T cell death[1]
Tim-1+ B cells mouse Tim−1+CD19+ production of IL-10, enhance Th2 and Treg responses, regulation of Th1 and Th17 cells during inflammation[1][18]
Transitional 2-marginal zone precursor cells mouse CD19+CD21hiCD23hi production of IL-10, suppression of effector CD4+, CD8+ T cells and induction of Treg cells[1][2][19]

Mechanisms of action

Structure of interleukin 10 (IL-10). Key player in Breg biology.

There are several mechanisms of Breg action. Nevertheless, the most examined mechanism is the production of IL-10. IL-10 has strong anti-inflammatory effects.

PD-1 and PD-L1. PD-1+ Bregs have been shown to suppress CD4+ and CD8+ T cell activity and induce Tr1 cells, while PD-L1 Bregs were reported to inhibit NK and CD8+ T cell cytotoxicity.[3] Some Bregs also express additional suppressive molecules such as CD39, CD73, and aryl hydrocarbon receptor.[1]

Activation

Resting B lymphocytes do not produce cytokines. After the response to antigen or different stimuli such as

CD40 ligand and/or TLR9 signals has been shown to induce B10 generation and the emergence of IL-10 producing plasmablasts during inflammatory processes.[3]

Autoimmune diseases

Bregs are studied in several human autoimmune diseases such as multiple sclerosis (MS), rheumatoid arthritis, SLE, type 1 diabetes, or Sjögren's syndrome. Generally, Breg cells seem to be important in preventing autoimmune diseases and are often reported reduced or with impaired inhibitory abilities in autoimmunity.[1][28]

Multiple sclerosis

The main reported mechanism of Breg reduction of MS is the production of IL-10, IL-35, and TGF- β. Bregs have been extensively studied in the mouse model of multiple sclerosis - EAE, where the depletion of Bregs worsened the disease and increased the number of

autoreactive T cells, but it is not clear whether the frequencies of Breg cells are altered in MS patients. Although one study reported normal Breg frequencies in MS patients, a few others have observed a decreased amount of Breg cells in patients. It has been reported that an approved medication for MS treatment Glatiramer acetate increases Breg frequencies and enhances their function. Similarly, Alemtuzumab, which is an antibody that binds CD52 of T and B cells and causes apoptosis or cell lysis, increases the frequency of Bregs in patients with relapsing MS.[1]

Systemic Lupus Erythematosus

It has been observed that patients with SLE have deficiencies in the function of Bregs. Bregs isolated from patients had been reported to lose their regulatory capacity and be unable to inhibit the expression of pro-inflammatory cytokines IFN-γ and TNF-α by CD4+ T cells compared to Bregs from healthy donors. Several studies have also noted a decrease in the percentage of IL-35+and IL-10+ Bregs cells in SLE patients.[1][29]

Type 1 Diabetes

In mouse models, IL-10-producing Bregs have been shown to control autoimmune diabetes. In type 1 diabetes (T1D), the evidence suggests that IL-10–producing Bregs are numerically and functionally defective in patients compared to healthy donors. Bregs in T1D have decreased production of IL-10 and are unable to suppress Th1 and Th17 immune responses. Moreover, these defective Bregs are unable to convert naive CD4+ T cells in Tregs.[19][28]

Tumors

Tumor-infiltrating B lymphocytes consist of various phenotypes, including both effector and regulatory B cells. IL-10 or Granzyme B-producing Bregs have been detected in various human cancers. Additionally, most studies have reported a positive correlation between Breg cells and Treg cells, which indicated an interaction between these subsets.

gastric cancer, breast cancer, head and neck squamous carcinoma, and esophageal squamous carcinoma. The evidence suggests an immunosuppressive Breg role in cancer and it is possible that cancerous proliferation uses Bregs for its escape from the immune response.[30]

Transplantation

It has been reported that patients undergoing kidney transplantation who were subjected to B-cell depletion therapy showed a higher incidence of graft rejection. The evidence shows that immunosuppressive properties of Bregs might play an essential role in allotransplants. Murine models of allotransplantation showed that Bregs increased the duration of allograft survival and controlled Th17, Tfh, and follicular regulatory T-cell differentiation.[1] In other types of transplants, B cells can participate both in tolerance and in transplant rejection, depending on the origin of the Breg subpopulation.[32]

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