Human regulatory B cells suppress autoimmune disease primarily via interleukin-37

Regulatory B cells (Bregs) are crucial for maintaining homeostasis and controlling inflammation. Although interleukin (IL)-10 has been traditionally suggested as the primary suppressive mechanism of Bregs in both mice and humans, the key functional differences between Bregs in these two species, particularly in the context of disease, is still largely unresolved. IL-37, the latest described immunosuppressive cytokine, is produced in humans but not in mice. Herein we identified the characteristics and functions of IL-37-producing Bregs, that naturally exist in human and can be induced by recombinant IL-37 (rIL-37) and/or Toll-like receptor 9 agonist CpG via different mechanisms. rIL-37 alone is sufficient to prompt IL-37, but not IL-10, production and proliferation of Bregs, whereas CpG elicits IL-37 expression in Bregs independently of IL-10, but dependent on HIF-1α which binds on the enhancer/promoter of the IL-37 gene. Functionally, IL-37⁺ Bregs exhibit superior anti-inflammatory efficacy than IL-37^- Bregs in vitro, as well as in psoriasis and colitis models. However, the frequency of IL-37⁺ Bregs is reduced in patients with psoriasis. Thus, IL-37⁺ Bregs hold significant therapeutic potential for treating various inflammatory disorders, including psoriasis and colitis.