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B lymphocytes can suppress immunity through interleukin (IL)-10 production in infectious, autoimmune, and malignant diseases. Here, we have identified a natural plasma cell subset that distinctively expresses the inhibitory receptor LAG-3 and mediates this function in vivo. These plasma cells also express the inhibitory receptors CD200, PD-L1, and PD-L2. They develop from various B cell subsets in a B cell receptor (BCR)-dependent manner independently of microbiota in naive mice. After challenge they upregulate IL-10 expression via a Toll-like receptor-driven mechanism within hours and without proliferating. This function is associated with a unique transcriptome and epigenome, including the lowest amount of DNA methylation at the Il10 locus compared to other B cell subsets. Their augmented accumulation in naive mutant mice with increased BCR signaling correlates with the inhibition of memory T cell formation and vaccine efficacy after challenge. These natural regulatory plasma cells may be of broad relevance for disease intervention.LAG-3 expression identifies natural regulatory plasma cellsLAG-3+CD138hi plasma cells express IL-10 within hours of stimulationLAG-3+CD138hi plasma cells have a unique epigenome poised to express IL-10LAG-3+CD138hi plasma cells develop via an antigen-specific mechanismPlasma cells secrete antibodies and play a key role in host defense against infection. Lino et al. identify a novel subset of natural regulatory plasma cells characterized by the expression of LAG-3 that develops at steady state independently of microbiota, and respond to innate stimulation by producing immunosuppressive IL-10.