B10 cell regulation of health and disease

Abstract

While B cells are traditionally regarded as promoters of the immune response via antibody secretion and pro-inflammatory cytokine production, recent studies have also confirmed an important role for B-cell-mediated negative regulation of immunity. Tremendous advances in the characterization of the mechanisms by which regulatory B cells function has led to the identification of a novel subset of regulatory B cells known as B10 cells, which regulate immune responses through the production of the anti-inflammatory cytokine interleukin-10 (IL-10). B10 cells are best defined by their functional ability to produce IL-10, as they are not confined to any particular phenotypic subset. B10 cells function in an antigen-specific manner that requires cognate interactions with T cells in vivo to regulate immune responses and have been demonstrated to be potent regulators of allergic and autoimmune disease, cancer, infection, and transplant rejection. Importantly, the recent discovery of human B10 cells has accelerated this field to the forefront of clinical research where the possibility of harnessing the regulatory potential of B10 cells for treatment of aberrant immune responses and diseases may become feasible.

Keywords: B cells; B10 cells; IL-10; autoimmunity; immunosuppression.

Fig. 1. Model for mouse B10 cell development

After B cells encounter the correct self or foreign antigen in vivo, appropriate levels of B-cell antigen receptor (BCR) signaling induce a small subset of B cells to progress down a developmental program that leads to IL-10 production. B10 progenitor (B10pro) cells do not express IL-10 but can become competent to do so after culture with agonistic CD40 monoclonal antibody (mAb) or lipopolysaccharide (LPS). Once B10pro cells become IL-10 competent, they are functionally defined as B10 cells. B10 cells do not express measurable IL-10 but are primed for transcription of the il10 locus. Stimulation of B10 cells with either phorbol-12-myristate-13-acetate and ionomycin or LPS induces the acute production of IL-10 transcripts and cytoplasmic IL-10 protein that accumulates to measurable levels within 5 h when monensin is present. Once B10 cells begin to secrete IL-10, they are functionally defined as B10 effector (B10eff) cells, which are rarely visualized in vivo. Based on their cell surface phenotypes, B10pro and B10 cells are likely to be chronically stimulated through their BCRs but require additional signals to become B10eff cells that produce IL-10, which can include LPS or CpG. Following transient IL-10 production in vivo, some B10eff cells acquire cell surface markers found of plasmablasts and differentiate into plasma cells that secrete polyreactive, autoreactive or self-reactive antibodies depending on their BCR specificity. Alternatively, the culture of spleen or blood B cells with NIH-3T3 cells expressing cell surface CD154 and BLyS in the presence of IL-4 for 4 days can induce B10pro cell expansion and the development of proliferating B10 cells when stimulated IL-21 for 5 days, resulting in the in vitro generation of B10eff cells.

Fig. 2. Model for B10 cell regulation of in vivo adaptive and innate immune responses following antigen-specific cognate interactions with T cells

To become B10eff cells and secrete IL-10 in vivo, B10 progenitor (B10pro) cells must (1) receive appropriate signals through B-cell antigen receptor interactions with antigen. These B cells are presumed to display antigenic peptides through their cell surface MHC class II (MHC-II) molecules (2), which facilitate their cognate interactions with peptide-specific CD4⁺ T cells (3). The antigen-specific T cells become activated and express CD154, which binds CD40 on the cognate B cells and induces B10 cell maturation and IL-10 competence. T-cell receptor (TCR) and CD154 engagement induces T-cell IL-21 production (3), which then acts locally on B10 cell IL-21 receptors (IL-21R) to promote IL-10-secreting B10 effector (B10eff) cell generation (4). IL-10 production by B10eff cells in the local microenvironment negatively regulates adaptive immune responses by inhibiting antigen-specific T cells (5) and inhibiting innate macrophage function (Mac, 6) during immune responses.