IL-10-producing regulatory B cells (B10 cells) in autoimmune disease

Abstract

B cell abnormalities contribute to the development and progress of autoimmune disease. Traditionally, the role of B cells in autoimmune disease was thought to be predominantly limited to the production of autoantibodies. Nevertheless, in addition to autoantibody production, B cells have other functions potentially relevant to autoimmunity. Such functions include antigen presentation to and activation of T cells, expression of co-stimulatory molecules and cytokine production. Recently, the ability of B cells to negatively regulate cellular immune responses and inflammation has been described and the concept of regulatory B cells has emerged. A variety of cytokines produced by regulatory B cell subsets have been reported, with IL-10 being the most studied. In this review, this specific IL-10-producing subset of regulatory B cells has been labeled B10 cells to highlight that the regulatory function of these rare B cells is mediated by IL-10, and to distinguish them from other B cell subsets that regulate immune responses through different mechanisms. B10 cells are a functionally defined subset currently identified only by their competency to produce and secrete IL-10 following appropriate stimulation. Although B10 cells share surface markers with other previously defined B cell subsets, currently there is no cell surface or intracellular phenotypic marker or set of markers unique to B10 cells. The recent discovery of an effective way to expand B10 cells ex vivo opens new horizons in the potential therapeutic applications of this rare B cell subset. This review highlights the current knowledge on B10 cells and discusses their potential as novel therapeutic agents in autoimmunity.

Figure 1

Linear differentiation model of B10 cell development in vivo in mice and humans. B10 cells originate from a progenitor population (B10_PRO). In mice, B10_PRO cells are found in the CD1d⁻CD5⁻ adult blood and lymph node B cell subsets and within the CD1d⁻CD5⁺ neonatal spleen and adult peritoneal cavity B cell subsets. CD40 stimulation induces B10_PRO cells to become competent for IL-10 expression, while lipopolysaccharide (LPS) induces B10_PRO cells to become competent for IL-10 expression and induces B10 cells to produce and secrete IL-10. CD1d^hiCD5⁺ IL-10-competent B10 cells in the adult spleen are induced to express IL-10 following stimulation with phorbol esters (phorbol-12-myristate-13-acetate (PMA)) and ionomycin or LPS plus PMA and ionomycin for 5 hours. Following a transient period of IL-10 expression, a small subset of B10 cells can differentiate into antibody-secreting plasma cells (PC). B10 cells also possibly differentiate into memory B10 cells (B10_M). B10 cell development in humans appears to follow the differentiation scheme observed in mice. B10 cells and B10_PRO cells have been identified in human newborn and adult blood. B10+B10_PRO cells in adult human blood express CD27 and CD24. Whether human B10 cells further differentiate into PCs or B10_M remains to be determined. Solid arrows, known associations; dashed arrows, speculated associations. MHC-II, major histocompatibility complex class II.

Figure 2

B10 cell regulatory effects in autoimmune disease. In this model, unidentified autoantigens (auto-Ags) drive early development of B10_PRO cells. Following exposure to CD40 ligation and/or Toll-like receptor (TLR) ligands (lipopolysaccharide (LPS), CpG), B10_PRO cells mature into B10 cells that can actively secrete IL-10 and regulate both innate and adaptive immune responses. IL-21R signaling along with major histocompatibility complex class II (MHC-II) and CD40 cognate interactions with CD4⁺ T cells, although not needed for B10 cell development, are necessary for B10 cell effector functions and result in antigen-specific responses. B10 cells regulate macrophage function by decreasing their activation, phagocytosis and cytokine and nitric oxide (NO) production. In antigen-presenting cells (APCs), B10-cell-negative regulation of antigen presentation, expression of co-stimulatory molecules (such as CD86) and proinflammatory cytokine production limits T cell activation. In CD4⁺ T helper (T_H) cells, B10 cells skew responses towards a T_H2 phenotype and away from T_H1 and T_H17 responses. The negative regulatory effects of B10 cells thereby limit inflammatory responses and subsequent tissue damage. Arrows with solid outline, known associations; arrows with dashed outline, speculated associations.