Implications of B10-like cell expansion in a model of impaired receptor editing

项目总结/文摘

PROJECT SUMMARY/ABSTRACT Although B cells are best known for providing humoral immunity through the production of antigen-specific antibodies, accumulating evidence suggests some B cell subsets can function to negatively regulate inflammatory responses by producing the immunosuppressive cytokine IL10. Perhaps the best characterized of these subsets is the B10 B cell, which is distinctive for its CD5+CD1dhiCD19hi phenotype and ability to secrete IL10 in response to mitogenic stimuli. B10 B cells are thought to promote antigen-specific suppression of autoreactive T cells through an IL10 (B cell) – IL21 (T cell) feedback loop established by cognate B cell-T cell interactions. Interestingly, some CD5+ B cell populations have a propensity to react with membrane- associated self-antigens and may also produce IL10 like B10 B cells. Furthermore, certain diseases associated with expanded CD5+ B cells, such as chronic lymphocytic leukemia and Sjögren’s syndrome, show an increased incidence of autoimmune cytopenias that occur when antibodies attack the host’s own cells. Together, these data raise the possibility that the IL10-dependent feedback mechanism may function in reverse to help constrain B cells reactive to membrane antigens, and that breakdown of this regulatory loop may cause B cell-intrinsic autoimmune manifestations. We previously generated transgenic mice (called dnRAG1 mice) which exhibit a receptor editing defect used to alter B cell receptor specificity away from self- reactivity. These animals show an expanded CD5+ B cell population and impaired antibody production. We have found that dnRAG1 CD5+ B cells share the immunophenotype and IL10-competence of B10 B cells, leading us to hypothesize that a failure to successfully edit B cell receptor specificity against certain self- antigens may cause the B cell to acquire B10-like properties to suppress B cell-intrinsic autoimmunity. Consistent with this hypothesis, we show here that IL10-deficiency in dnRAG1 mice leads to elevated IgM production. This hypothesis will be further tested by analyzing wild-type and dnRAG1 mice on IL10+/+ and IL10-/- backgrounds to compare spontaneous and stimulation-induced antibody levels, autoantigen reactivity profiles, immunoglobulin variable gene usage patterns, and the frequency of IgM antibody-producing cells. We will also determine whether adoptively transferring CD5+ B cells from IL10+/+ dnRAG1 mice into IL10-/- dnRAG1 mice can restore immune suppression in these animals. Furthermore, we will test whether impaired receptor editing in mice expressing a site-directed phosphatidylcholine (PtC)-specific heavy chain transgene enhances CD5+ B cell accumulation and IL10-competence, and suppresses total or PtC-specific IgM production. The results obtained from this study may reveal an important new mechanism for how B cell-intrinsic autoimmunity against certain self-antigens are suppressed, and will identify autoantigens that may be subjected to tolerance induction by receptor editing. This work may also suggest an etiology for certain autoimmune manifestations, like cytopenias, that can arise as a clinical complication in diseases associated with expanded CD5+ B cells.