Regulatory B (Breg) cells are a subset of B cells that plays a suppressive role in modulating immune response through its ability to secrete interleukin-10 (IL-10), an anti-inflammatory cytokine. Results from previous studies demonstrated that depletion of Breg cells exacerbates the symptoms of autoimmune diseases in mice include experimental autoimmune encephalitis (EAE). However, little is known about the mechanisms that guide the differentiation of Breg cells. B lymphocyte-induced maturation protein-1 (Blimp-1) is the key transcriptional repressor important for regulating the differentiation of B cells into antibody secreting plasma cells. Blimp-1 also involves in the development and differentiation of other immune cell lineages. Previous studies showed that Blimp-1-deficient regulatory T cells were defective in controlling the development of colitis through regulating IL-10 production.
We found that Blimp-1 expression is enriched in IL-10 producing Breg cells. Compared with wild type (WT) B cells, stimulation of primary splenic B cells from Blimp-1 deficient mice with LPS or anti-CD40 produces significantly higher frequency of IL-10 producing Breg and B10 (CD19+CD1dhiCD5+) cells, but only marginally influences cell proliferation and has no effects on apoptosis. In vivo, LPS stimulation also increased the expansion of B10 cells in Blimp-1 deficient mice, as compared with that in WT mice. In response to LPS or anti-CD40 stimulation in culture, Blimp-1 deficient B10 cells express increased Il-10 mRNA and protein at early time point, but lower Il-10 mRNA and protein expression at later time point, as compared with stimulated WT B10 cells. Mechanistically, we found Blimp-1 directly bind to Il-10 gene promoter and suppresses Il-10 transcription in B cells. To examine if Blimp-1 affects Breg function, we are testing if the pathogenesis of EAE will be affected after adoptive transfer of Breg cells lacking Blimp-1.
Keywords: Interleukin-10, regulatory B cell, Blimp-1, EAE