Regulatory B cell

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Regulatory B cells (Bregs or Breg cells) represent a small population of B cells that participates in immunomodulation and in the suppression of immune responses. The population of Bregs can be further separated into different human or murine subsets such as B10 cells, marginal zone B cells, Br1 cells, GrB+B cells, CD9+ B cells, and even some plasmablasts or plasma cells. Bregs regulate the immune system by different mechanisms. One of the main mechanisms is the production of anti-inflammatory cytokines such as interleukin 10 (IL-10), IL-35, or transforming growth factor beta (TGF-β). Another known mechanism is the production of cytotoxic Granzyme B. Bregs also express various inhibitory surface markers such as programmed death-ligand 1 (PD-L1), CD39, CD73, and aryl hydrocarbon receptor. The regulatory effects of Bregs were described in various models of inflammation, autoimmune diseases, transplantation reactions, and in anti-tumor immunity. [1] [2] [3]

Contents

History

In the 1970s it was noticed that Bregs could suppress immune reaction independently of antibody production. [4] In 1996 Janeway's group observed an immunomodulation of experimental autoimmune encephalomyelitis (EAE) by B cells. [5] Similar results were shown in a model of chronic colitis one year later. [6] Then a role of Bregs was found in many mouse models of autoimmune diseases as rheumatoid arthritis [7] or 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 plasmablasts. Whether Breg cells uniquely derive from a specific progenitor or originate within conventional B cell subsets is still an open question. [1] [9] Unfortunately, Breg cells are more difficult to define than regulatory T cells (Tregs) since they lack a lineage marker analogous to the Treg cell marker - FOXP3. [10] Bregs share many markers with various B cell subsets due to their origin. Human and murine Bregs can be further separated into many subsets due to their different mechanism of action and distinct expression of key surface markers (table below). It is estimated that IL-10 producing B cell subpopulations can constitute up to 10% of circulating human B cells. [11] There is still no clear consensus on the classification and definition of Breg cells. [1] Mouse Bregs were mainly CD5 and CD1d positive in the model of EAE or after the exposition of Leishmania major . [12] [13] By contrast, mouse Bregs in model of collagen-induced arthritis (CIA) were mainly CD21 and CD23 positive. [14] Bregs were found in humans, too. Markers of peripheral blood Bregs were molecules CD24 and CD38. [15] However, peripheral blood Bregs were mostly CD24 and CD27 positive after cultivation with anti-CD40 antibody and CpG bacterial DNA. [16] They were also positive for CD25, CD71 and PD-L1 after stimulation by CpG bacterial DNA and through TLR9. [17]

Breg subsets identified in human or mice
SubsetSpeciesPhenotypeFunction
B10 cells human, mouseCD24hiCD27+ (human), CD5+CD1dhi (mouse)production of IL-10, suppression of effector CD4+ T cells, monocytes, and DCs [1] [2]
Plasmablasts human, mouseCD19+CD24hiCD27int (human), CD138+CD44hi (mouse)production of IL10 and TGF-β, suppression of DCs and effector CD4+ T cells [1] [2] [3]
Plasma cells mouseCD138+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, mouseCD19+CD21hiCD23−production of IL-10, induction of Treg cells, suppression of effector CD4+ and CD8+ T cells [1] [2] [3] [11]
Br1 cellshumanCD19+CD25hiCD71hi CD73−production of IL-10, suppress inflammatory responses, induction of Treg cells and promotion of IgG4 production [1]
GrB+B cellshumanCD19+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 cellshuman, mouseCD19+CD9+production of IL-10, suppression of Th2 and Th17 inflammation [1]
CD5+CD1d+ cellshumanCD19+CD5+CD1dhiproduction of IL-10, suppression of Th17 response [1]
B1a cellsmouseCD19+CD5+production of IL-10, suppression of TLR-mediated inflammation [1]
Killer B cellsmouseCD19+CD5+FasL+induction of T cell death [1]
Tim-1+ B cellsmouseTim−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 cellsmouseCD19+CD21hiCD23hiproduction 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. PDB 1ilk EBI.jpg
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. [20] [21] It inhibits (or suppresses) inflammatory reactions mediated by T cells, especially Th1 and Th17 type immune reactions. This was shown for example in the models of EAE, [22] CIA [23] or contact hypersensitivity. [24] 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. [25] By production of IL-10, Bregs are also capable of conversion of naïve CD4+ T cells into Tregs and IL-10-secreting type 1 regulatory CD4+ T cells. This has been observed in various experimental models as well as chronically virus-infected patients. [3] Another mechanism of Breg suppression is the production of transforming growth factor (TGF-β), an anti-inflammatory cytokine. [20] The role of Bregs producing TGF-β was found in the mouse models of SLE [8] and diabetes. [26] The last anti-inflammatory cytokine produced only by some Bregs is IL-35, which plays a role in Treg conversion. Breg cells are capable of releasing IL-35 containing exosomes. It is not yet clear whether IL-10 and IL-35-producing Bregs correspond to separate populations or display some degree of overlap. [3] Besides the production of immunomodulatory cytokines, Bregs also release cytotoxic granzyme B involved in the degradation of the T cell receptor and T cell apoptosis. [11] Another mechanism of Breg suppression involves surface molecules such as FasL, which induces T cell death, [27] or 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 lipopolysaccharide (LPS) pro- and anti-inflammatory cytokines TNFα, IL-1β, IL-10 and IL-6 are produced. This indicates that the Breg must be stimulated to produce suppressive cytokines. There are two types of signals to activate Breg, namely signals generated by external pathogens (PAMPs) and endogenous signals produced by the action of body cells. PAMPs are recognized by the toll-like receptors (TRLs). TLRs trigger a signal cascade at the end of which is the production of effector cytokines. Bregs are mainly generated after the recognition of TLR4 or TLR9 ligands - LPS and CpG. The main endogenous signal is the stimulation of the surface molecule CD40. [1] [2] Some anti-inflammatory factors, such as IL-35 and retinoic acid have also been proposed to induce Breg phenotype. Additionally, cytokine IL-21 together with 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. [10] It has been observed that higher frequencies of IL-10-producing B cells were observed in late-stage disease samples than in early-stage samples of esophageal cancer. [30] Leukemia B cells spontaneously produce large amounts of IL-10. [31] Moreover, increased levels of Bregs were detected in the peripheral blood and bone marrow of patients with acute myeloid leukemia. IL-10-producing Bregs are also present in 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]

Related Research Articles

<span class="mw-page-title-main">T helper cell</span> Type of immune cell

The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4+ cells are mature Th cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4+ cells determines susceptibility to a broad class of autoimmune diseases.

The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. Treg cells express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4+ cells. Because effector T cells also express CD4 and CD25, Treg cells are very difficult to effectively discern from effector CD4+, making them difficult to study. Research has found that the cytokine transforming growth factor beta (TGF-β) is essential for Treg cells to differentiate from naïve CD4+ cells and is important in maintaining Treg cell homeostasis.

<span class="mw-page-title-main">FOXP3</span> Immune response protein

FOXP3, also known as scurfin, is a protein involved in immune system responses. A member of the FOX protein family, FOXP3 appears to function as a master regulator of the regulatory pathway in the development and function of regulatory T cells. Regulatory T cells generally turn the immune response down. In cancer, an excess of regulatory T cell activity can prevent the immune system from destroying cancer cells. In autoimmune disease, a deficiency of regulatory T cell activity can allow other autoimmune cells to attack the body's own tissues.

Immune tolerance, or immunological tolerance, or immunotolerance, is a state of unresponsiveness of the immune system to substances or tissues that would otherwise have the capacity to elicit an immune response in a given organism. It is induced by prior exposure to that specific antigen and contrasts with conventional immune-mediated elimination of foreign antigens. Tolerance is classified into central tolerance or peripheral tolerance depending on where the state is originally induced—in the thymus and bone marrow (central) or in other tissues and lymph nodes (peripheral). The mechanisms by which these forms of tolerance are established are distinct, but the resulting effect is similar.

<span class="mw-page-title-main">Interleukin 23 subunit alpha</span>

Interleukin-23 subunit alpha is a protein that in humans is encoded by the IL23A gene. The protein is also known as IL-23p19. It is one of the two subunits of the cytokine Interleukin-23.

<span class="mw-page-title-main">Interleukin 21</span> Mammalian protein found in humans

Interleukin 21 (IL-21) is a protein that in humans is encoded by the IL21 gene.

<span class="mw-page-title-main">Interleukin 17</span> Group of proteins

Interleukin 17 family is a family of pro-inflammatory cystine knot cytokines. They are produced by a group of T helper cell known as T helper 17 cell in response to their stimulation with IL-23. Originally, Th17 was identified in 1993 by Rouvier et al. who isolated IL17A transcript from a rodent T-cell hybridoma. The protein encoded by IL17A is a founding member of IL-17 family. IL17A protein exhibits a high homology with a viral IL-17-like protein encoded in the genome of T-lymphotropic rhadinovirus Herpesvirus saimiri. In rodents, IL-17A is often referred to as CTLA8.

T helper 17 cells (Th17) are a subset of pro-inflammatory T helper cells defined by their production of interleukin 17 (IL-17). They are related to T regulatory cells and the signals that cause Th17s to actually inhibit Treg differentiation. However, Th17s are developmentally distinct from Th1 and Th2 lineages. Th17 cells play an important role in maintaining mucosal barriers and contributing to pathogen clearance at mucosal surfaces; such protective and non-pathogenic Th17 cells have been termed as Treg17 cells.

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Interleukin 35 (IL-35) is a recently discovered anti-inflammatory cytokine from the IL-12 family. Member of IL-12 family - IL-35 is produced by wide range of regulatory lymphocytes and plays a role in immune suppression. IL-35 can block the development of Th1 and Th17 cells by limiting early T cell proliferation.

Gamma delta T cells are T cells that have a γδ T-cell receptor (TCR) on their surface. Most T cells are αβ T cells with TCR composed of two glycoprotein chains called α (alpha) and β (beta) TCR chains. In contrast, γδ T cells have a TCR that is made up of one γ (gamma) chain and one δ (delta) chain. This group of T cells is usually less common than αβ T cells. Their highest abundance is in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs).

<span class="mw-page-title-main">Interleukin-17A</span> Protein-coding gene in the species Homo sapiens

Interleukin-17A is a protein that in humans is encoded by the IL17A gene. In rodents, IL-17A used to be referred to as CTLA8, after the similarity with a viral gene.

T helper 3 cells (Th3) are a subset of T lymphocytes with immunoregulary and immunosuppressive functions, that can be induced by administration of foreign oral antigen. Th3 cells act mainly through the secretion of anti-inflammatory cytokine transforming growth factor beta (TGF-β). Th3 have been described both in mice and human as CD4+FOXP3− regulatory T cells. Th3 cells were first described in research focusing on oral tolerance in the experimental autoimmune encephalitis (EAE) mouse model and later described as CD4+CD25−FOXP3−LAP+ cells, that can be induced in the gut by oral antigen through T cell receptor (TCR) signalling.

<span class="mw-page-title-main">Fiona Powrie</span> Sidney Truelove Professor of Gastroenterology

Dame Fiona Magaret Powrie is currently the head of the Kennedy Institute of Rheumatology at the University of Oxford. Formerly she was the inaugural Sidney Truelove Professor of Gastroenterology at the University of Oxford. She is also head of the Experimental Medicine Division of the Nuffield Department of Clinical Medicine.

Regulatory macrophages (Mregs) represent a subset of anti-inflammatory macrophages. In general, macrophages are a very dynamic and plastic cell type and can be divided into two main groups: classically activated macrophages (M1) and alternatively activated macrophages (M2). M2 group can further be divided into sub-groups M2a, M2b, M2c, and M2d. Typically the M2 cells have anti-inflammatory and regulatory properties and produce many different anti-inflammatory cytokines such as IL-4, IL-33, IL-10, IL-1RA, and TGF-β. M2 cells can also secrete angiogenic and chemotactic factors. These cells can be distinguished based on the different expression levels of various surface proteins and the secretion of different effector molecules.

Tolerogenic therapy aims to induce immune tolerance where there is pathological or undesirable activation of the normal immune response. This can occur, for example, when an allogeneic transplantation patient develops an immune reaction to donor antigens, or when the body responds inappropriately to self antigens implicated in autoimmune diseases. It must provide absence of specific antibodies for exactly that antigenes.

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<span class="mw-page-title-main">Type 3 innate lymphoid cells</span>

Type 3 innate lymphoid cells (ILC3) are immune cells from the lymphoid lineage that are part of the innate immune system. These cells participate in innate mechanisms on mucous membranes, contributing to tissue homeostasis, host-commensal mutualism and pathogen clearance. They are part of a heterogeneous group of innate lymphoid cells, which is traditionally divided into three subsets based on their expression of master transcription factors as well as secreted effector cytokines - ILC1, ILC2 and ILC3.

Tolerogenic dendritic cells are heterogenous pool of dendritic cells with immuno-suppressive properties, priming immune system into tolerogenic state against various antigens. These tolerogenic effects are mostly mediated through regulation of T cells such as inducing T cell anergy, T cell apoptosis and induction of Tregs. Tol-DCs also affect local micro-environment toward tolerogenic state by producing anti-inflammatory cytokines.

B10 cells are a sub-class of regulatory B-cells that are involved in inhibiting immune responses in both humans and mice. B10 cells are named for their ability to produce inhibitory interleukin: Interleukin-10 (IL-10). One of their unique abilities is that they suppress the innate and adaptive immune signals, making them important for regulating the inflammatory response. Like the B cell, the B10 cell requires antigen specific binding to the surface of CD5 receptor to illicit a response from the T-cell. Once an antigen binds to the CD19 receptor, immediate downregulation in B-cell receptor (BCR) signal expression occurs and mediates the release of IL-10 cytokines. In mice and humans, B10 cells are distinguishable in their expression of measurable IL-10 due to the lack of unique cell surface markers expressed by regulatory B cells. However, IL-10 competence is not limited to any one subset of B cells. B10 cells do not possess unique phenotypic markers or transcription factors for further identification. B10 cells predominantly localize in the spleen, though they are also found in the blood, lymph nodes, Peyer's patches, intestinal tissues, central nervous system, and peritoneal cavity. B10 cells proliferate during inflammatory and disease responses.

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