Immunosuppressive Mechanisms of Regulatory B Cells

Abstract

Regulatory B cells (Bregs) is a term that encompasses all B cells that act to suppress immune responses. Bregs contribute to the maintenance of tolerance, limiting ongoing immune responses and reestablishing immune homeostasis. The important role of Bregs in restraining the pathology associated with exacerbated inflammatory responses in autoimmunity and graft rejection has been consistently demonstrated, while more recent studies have suggested a role for this population in other immune-related conditions, such as infections, allergy, cancer, and chronic metabolic diseases. Initial studies identified IL-10 as the hallmark of Breg function; nevertheless, the past decade has seen the discovery of other molecules utilized by human and murine B cells to regulate immune responses. This new arsenal includes other anti-inflammatory cytokines such IL-35 and TGF-β, as well as cell surface proteins like CD1d and PD-L1. In this review, we examine the main suppressive mechanisms employed by these novel Breg populations. We also discuss recent evidence that helps to unravel previously unknown aspects of the phenotype, development, activation, and function of IL-10-producing Bregs, incorporating an overview on those questions that remain obscure.

Patients with Common Variable Immunodeficiency Complicated by Autoimmune Phenomena Have Lymphopenia and Reduced Treg, Th17, and NK Cells

“…Bregs play a critical role in immune homeostasis and tolerance. Despite extensive efforts to phenotypically characterize Bregs, we still lack a definitive set of phenotypic markers or a signature transcriptional regulator (equivalent to FoxP3 Tregs) that enables us to comprehensibly identify Bregs [ 44 ]. In our study, Bregs were identified as CD19+ CD5+ CD1d high .…”

“…CD1d is a major phenotypic marker highly expressed in many Breg cells, and it may play a crucial role in Breg-cell-mediated suppression [ 45 ]. The upregulation of CD1d on B cells is associated with B-cell-mediated protection against inflammation [ 44 , 46 ]. In our study, we observed a tendency for decreased Bregs in CVID-C patients; however, this was not statistically significant.…”

Role of Immune Cells in Patients with Hepatitis B Virus-Related Hepatocellular Carcinoma

“…In chronic inflammatory conditions such as CHB, B cells can differentiate into another distinct subset, regulatory B cells (Breg cell), which increase the production of immunosuppressive cytokines such as IL-10 and TGF-β and present inhibitory molecules such as PD-1 [ 84 , 85 , 86 ]. Breg cells orchestrate an immunosuppressive environment to limit tissue damage in chronic inflammatory conditions; however, it eventually contributes to tumor evasion by the immune surveillance system [ 84 , 87 ]. In patients with HBV-related HCC, IL-10-expressing B cells preferentially presented with TIM-1 expression, and their frequency was negatively correlated with the frequencies of granzyme A, granzyme B, and perforin-expressing CD4+ T cells [ 88 ].…”

The PD-1/PD-L1 Checkpoint in Normal Germinal Centers and Diffuse Large B-Cell Lymphomas

“…There is accumulating evidence for the existence of a subset of B cells that can exert immune regulatory functions, termed regulatory B cells (Breg) [ 58 , 59 , 60 , 61 ]. The majority of studies on the inhibitory function of Bregs have focused on IL-10, IL-35 and TGF-β as key players that can repress the differentiation, proliferation and effector function of various cell types, like dendritic, CD4 + and CD8 + T cells [ 62 , 63 , 64 , 65 , 66 ].…”

“…One example are regulatory plasmocytes, B cells in terminal differentiation towards antibody secretor plasma cells that in the presence of some antigens can be transcriptionally reprogramed to produce high levels of inhibitory molecules as IL-10, PD-L1 and LAG-3, repressing both myeloid and lymphoid pro-inflammatory populations [ 74 , 75 ]. Other examples are protumorigenic Breg populations that can affect anti-tumour immune responses through different suppressive mechanisms [ 61 , 72 ]. Certain subsets of these tumour-infiltrating Breg cells can upregulate PD-1 expression in response to signaling from cancer cells, promoting T-cell dysfunction via IL-10 [ 76 ] or, independently of IL-10, via PD-L1 [ 77 ].…”