Regulatory B10 cells control immune responses via antigen-specific pathways

Abstract

Abstract B cells secrete antigen-specific antibodies during immune responses to neutralize pathogens and other threats. Despite this well-characterized pro-inflammatory B cell function, a rare subset of B cells (B10 cells) in both humans and mice are known to produce the inhibitory cytokine interleukin 10 (IL-10) and provide negative regulation of inflammation and T cell-dependent autoimmunity. B cell receptor (BCR)-derived signals are essential to regulatory B cell function as B10 cell suppression of disease is antigen-specific and requires cognate interactions with T cells. In addition, B10 cell development is blunted in mice with fixed BCR specificities, underscoring the key role that BCR signaling plays in the acquisition of B cell IL-10 competence. Given the importance of the BCR in both B10 cell development and function, we hypothesized that antigen-specific B10 cells are required for optimal disease suppression. Here we show by single-cell PCR that B10 cells derived from naive mice as well as from mice exposed to antigen express a diverse set of both heavy and light chain immunoglobulin genes that are predominantly without mutations. In addition, we demonstrate using IL-10 reporter mice that antigen-specific B10 cells are reliably expanded in vivo and that these antigen-specific B10 cells are required for optimal disease suppression upon adoptive transfer. Thus, B10 cells provide robust antigen-specific regulation of immune responses in vivo through diverse, unmutated BCRs.