SP0085 Regulatory B10 cells during inflammation, autoimmunity and cancer

B cells have the capacity to negatively regulate inflammation and cellular immune responses through a subset of regulatory B cells (B10 cells) that has been functionally defined in humans and mice by their ability to express IL-10. Regulatory B10 cells are found in the tissues of young naive mice at low frequencies (1-5%), but expand with inflammation and/or autoimmunity. Human B10 cells are functionally comparable to their mouse counterparts, represent a subset of the circulating CD24 hi CD27 + “memory” B cell subpopulation. B10 cells are generally rare in healthy individuals, but can expand significantly with inflammation and autoimmune disease. Although B10 cell development and immunoregulation are antigen-specific and require BCR signaling, functionally mature B10 cells can also be induced to express IL-10 in response to TLR signaling, thereby bridging adaptive and innate immunity. The capacity of B10 cells to express IL-10 is central to their ability to negatively regulate inflammation, and adaptive and innate immune responses. Specifically, human and mouse B10 cells negatively regulate monocytes, dendritic cells and T cell function in vitro and in vivo through the production of IL-10. Even small numbers of adoptively transferred regulatory B10 cells can dramatically suppress autoimmunity, T cell and monocyte activation and effector cell function in vivo through IL-10-dependent mechanisms. B10 cells are thereby remarkably potent negative regulators of autoimmunity in mouse models of contact hypersensitivity, multiple sclerosis, lupus, and arthritis. Small numbers of adoptively transferred regulatory B10 cells also dramatically suppress therapeutic lymphoma depletion by CD20 mAb in mice by inhibiting monocyte activation and effector function through IL-10-dependent mechanisms. B10 cells also maintain a capacity for plasma cell differentiation following a transient period of il10 transcription. The blimp1 and irf4 transcription factors are induced in B10 cells while pax5 and bcl6 are downregulated as a significant fraction of B10 cells completed the genetic and phenotypic program leading to antibody-secreting cell differentiation in vitro and in vivo . B10 cells represent a major source of serum IgM and IgG during adoptive transfer experiments, and produce antigen-specific, polyreactive and autoreactive antibody specificities that are consistent with their expression of a diverse antigen receptor repertoire. Thereby, B10 cells not only limit inflammation and immune responses by the transient production of IL-10, but may also facilitate clearance of their eliciting antigens through an inherent capacity to quickly generate polyreactive and/or antigen-specific antibodies during humoral immune responses. Yanaba, et al. A regulatory B cell subset with a unique phenotype controls T cell-dependent inflammatory responses. Immunity 2008; 28:639-650. Matsushita, et al. Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression. J Clin Invest. 2008; 118:3420-3430. DiLillo, et al. B10 and regulatory B cells balance immune responses during inflammation, autoimmunity and cancer. In: The Year in Immunology. Ann NY Acad Sci. 2010: 1183:38-57. Iwata, et al. Characterization of a rare IL-10-competent B cell subset in man that parallels mouse regulatory B10 cells. Blood . 2011; 117:530-541. Yanaba, et al. The development and function of regulatory B cells expressing IL-10 (B10 cells) requires antigen receptor diversity and TLR signals. J Immunol . 2009; 182:7459-7472. Horikawa, et al. Regulatory B lymphocyte production of IL-10 inhibits lymphoma depletion during CD20 immunotherapy in mice. J Clin Invest. 2011; 121:4205. Poe, et al. Amplified B lymphocyte CD40 signaling drives regulatory B10 cell expansion in mice. PLoS One 2011; 6: e22464. Maseda, et al. Regulatory B10 cells differentiate into antibody-secreting cells after transient IL-10 production in vivo . J Immunol. 2011; 188:1836-1048. Disclosure of Interest None Declared