The HMGB1 (C106A) mutation inhibits IL-10-producing CD19(hi)FcγRIIb(hi) B cell expansion by suppressing STAT3 activation in mice

Regulatory B cells have important roles in inflammation and autoimmune diseases. A newly discovered subpopulation of B cells with a CD19(hi)FcγRIIb(hi) phenotype inhibits the proliferation of CD4(+) T cells by secreting interleukin (IL)-10. The expansion of CD19(hi)FcγRIIb(hi) B cells in mouse spleen can be induced by lipopolysaccharide (LPS) or CpG oligodeoxynucleotide stimulation. However, the mechanism of CD19(hi)FcγRIIb(hi) B cell expansion and its role in inflammatory diseases are unclear. Here, we report that, under inflammatory conditions, the proliferation and immunosuppressive function of CD19(hi)FcγRIIb(hi) B cells were decreased in high mobility group box1 (HMGB1) C106A mutant mice, compared with wild-type mice. The HMGB1 (C106A) mutation in B cells reduced STAT3 phosphorylation, restricting the expansion and suppressive function of CD19(hi)FcγRIIb(hi) B cells. Compared with CD19(hi)FcγRIIb(hi) B cells from wild-type mice, CD19(hi)FcγRIIb(hi) B cells from Hmgb1 ((C106A)) mice significantly reduced the survival of mice with sepsis. Recombinant HMGB1 promoted the expansion of IL-10-producing CD19(hi)FcγRIIb(hi) B cells among LPS-activated B cells in vitro. Furthermore, the percentage of CD19(hi)FcγRIIb(hi) regulatory B cells in the peripheral blood was increased in patients with sepsis, compared with healthy controls. These findings implicate the role of HMGB1 in the expansion and immunosuppressive function of CD19(hi)FcγRIIb(hi) B cells.