Human regulatory B cells in health and disease: therapeutic potential

Abstract

Regulatory B cells (Bregs) modulate immune responses predominantly, although not exclusively, via the release of IL-10. The importance of human Bregs in the maintenance of immune homeostasis comes from a variety of immune-related pathologies, such as autoimmune diseases, cancers, and chronic infections that are often associated with abnormalities in Breg numbers or function. A continuous effort toward understanding Breg biology in healthy individuals will provide new opportunities to develop Breg immunotherapy that could prove beneficial in treating various immune-mediated pathologies. In this Review, we discuss findings regarding human Bregs, including their mechanisms of suppression and role in different disease settings. We also propose several therapeutic strategies targeting Bregs for better management of immune disorders.

Figure 1. Induction of Bregs.

IL-10–producing Bregs that express regulatory genes are generated as a consequence of immune activation. The signals that induce the differentiation of Bregs include inflammatory stimuli (via TLRs), costimulatory signals (CD40, CD80, CD86), microbiota, and cytokines (IFN-α/β, IL-1β, IL-6, IL-21, and BAFF).

Figure 2. Potential Breg-targeted therapies.

Therapeutic interventions targeting Bregs could provide improved approaches for the treatment of immune-mediated diseases. (i) Ex vivo expansion of Bregs. Stimulation of B cells isolated from patient-derived PBMCs to expand Bregs, followed by adoptive transfer of FACS-sorted Bregs, could suppress inflammation and reestablish tolerance. (ii) In vivo modulation to expand Bregs. The recent identification of stimuli that induce Breg differentiation provides new opportunities to induce a shift in B cells toward a more regulatory or antiinflammatory phenotype. (iii) Depletion of Bregs or Beffs. Targeted depletion of specific B cell subsets would provide more advantages over currently used total B cell depletion therapies in the treatment of cancers and other immune disorders.