TLR7 stimulation of T-betCD11cIgDCD27 double-negative 2 (DN2) B cells is crucial for autoantibody formation in systemic lupus erythematosus (SLE). Here, we show that administration of IL-4 for five weeks significantly reduced autoantibodies and T-betCD11c IgD B cells in autoimmune BXD2 mice treated with R848, a TLR7 agonist. Single-cell transcriptomics analysis indicates that following two doses of in vivo administration, IL-4 redirected development toward follicular, CD23 germinal center (GC), and DN4-like memory B cells compared to treatment with R848 alone. While IL-4 enhanced genes related to antigen processing and presentation, it also suppressed R848-induced Ki67 GC B cells in vivo. In vitro stimulation of SLE patient B cells with a DN2 polarizing cocktail revealed that IL-4 reduced the expression of interferon response and DN2 signature genes, promoting a population of CD23T-bet DN4 B population. These findings suggest that developmental reprogramming by IL-4 counteracts TLR7-promoted DN2 and GC B cells in SLE.
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