Induced regulatory B cells stably expressing interleukin-10 reverse central nervous system autoimmunity by targeting myeloid cells.

The lack of approaches to produce interleukin (IL)-10-producing B cells at high frequency has hampered mechanistic investigation into the generation, fate, and activity of these regulatory cells. We screened pharmacological compounds for their ability to induce IL-10 expression in B cells. One compound, N6, promoted stable IL-10 expression in >95% of B cells. Transfer of IL-10+ B cells induced remission of experimental autoimmune encephalomyelitis. N6-induced B cells accumulated in the central nervous system (CNS) and differentiated into IL-10+ plasma cells, promoting transcriptional and phenotypic changes in myeloid cells within the CNS. The therapeutic effect of IL-10+ B cell transfer was abrogated in mice lacking IL-10 receptor expression in long-lived myeloid cells, pointing to microglia as targets of B cell-derived IL-10. Importantly, an N6 analog corrected defective IL-10 expression in B cells from multiple sclerosis patients. Our findings establish a pharmacological strategy to generate IL-10+ B cells with therapeutic potential and identify microglia as critical targets for intercepting neuroinflammatory disease progression.