Abstract
B cells have been historically characterized as positive regulators of immune responses, but can also influence immune responses through numerous mechanisms other than antibody production. In one example, we and others have functionally identified a rare but specific subset of IL-10-competent regulatory B cells in humans and mice by their ability to secrete IL-10. We have labeled these B cells as “B10 cells” to identify them as the exclusive source of B-cell IL-10. The capacity of B10 cells to produce IL-10 is central to their ability to negatively regulate inflammation and autoimmune disease, as well as adaptive and innate immune responses. Rare B10 cell numbers often increase during inflammation and autoimmunity, particularly in some patients with active disease and autoimmune-prone mice. Nonetheless, the in vivo expansion of B10 cells in mice and patients responding to inflammation is inadequate to effectively control disease. However, the adoptive transfer of 1-2x105 spleen B10 cells from naïve or antigen-primed mice significantly inhibits disease initiation in mouse models of inflammation, autoimmune disease, and contact hypersensitivity. B10 cells are not overtly immunosuppressive, but instead have antigen-specific regulatory functions. Appropriate B-cell antigen receptor specificity and signals are required to drive B10 cell development and acquisition of IL-10 competence under physiological conditions in vivo. Following antigen-specific B10 cell development, their maturation into functional IL-10-secreting effector cells in vivo requires IL-21 and CD40-dependent cognate interactions with antigen-specific T cells. These critical checkpoints are likely to direct localized B10 cell IL-10 production to blunt antigen-specific T-cell responses during cognate B10:T cell interactions. These findings likely explain how antigen-specific B10 cell-effector function can exert such potent in vivo effects and selectively inhibit antigen-specific T-cell function during inflammation and autoimmunity without untoward immunosuppression. Human B10 cells are likely to have similar in vivo regulatory activities. In support of this, collaborative studies with Brice Weinberg and others have shown that human blood B10 cells and malignant cells from 90 percent of patients with chronic lymphocytic leukemia (CLL) share similar cell surface phenotypes and the capacity to express IL-10. Mouse B10 cells and malignant cells in the Tcl-1 transgenic mouse model of CLL also share similar phenotypes and the capacity to express IL-10. Of importance, CLL cell production of IL-10 appears to be dynamically regulated in mice and CLL patients are frequently immunosuppressed with abnormalities in both humoral and cellular immunity. Thus, B10 cells and CLL cells share regulatory properties. Insights into the molecular pathways that regulate antigen-specific B10 cell function in vivo have led to the development of an in vitro culture system that expands functionally-active mouse B10 cells (B10 effector cells) ex vivo by 4 million-fold. B10 effector cells resulting from this culture system secrete IL-10, retain their antigen-specific regulatory functions, and have demonstrated potent anti-inflammatory effects that effectively treat mice with established autoimmune disease. In mice, this culture system allows the generation of sufficient B10 effector cells from one mouse to treat 21,000 syngeneic mice with established disease. Thus, autologous B10 effector cells may eventually provide a new therapy that successfully treats patients with severe and refractory autoimmune disease, particularly those individuals for whom effective drugs have not been identified, as well as those who experience transplant rejection.
Disclosures:
Tedder: Angelica Therapeutics, Inc.: Consultancy, Equity Ownership; National Institutes of Health grants AI56363 and AI057157: Research Funding; Lymphoma Research Foundation: Research Funding.
Innate and Adaptive Immunity in Giant Cell Arteritis
