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. 2025 Jun:275:110472.
doi: 10.1016/j.clim.2025.110472. Epub 2025 Mar 9.

IL-4 alters TLR7-induced B cell developmental program in lupus

Changming Lu  1 , Shanrun Liu  1 , Min Gao  2 , Jose Rubio  1 , W Winn Chatham  3 , Hui-Chen Hsu  4 , John D Mountz  5
Affiliations

IL-4 alters TLR7-induced B cell developmental program in lupus

Changming Lu et al. Clin Immunol. 2025 Jun.

Abstract

TLR7 stimulation of T-bet+CD11c+IgD-CD27- 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-bet+CD11c+ 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 CD23+T-bet- DN4 B population. These findings suggest that developmental reprogramming by IL-4 counteracts TLR7-promoted DN2 and GC B cells in SLE.

Keywords: B cell(2); IL-4(3); TLR7(4); autoantibodies(6); lupus(1); transcriptomics(5).

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Conflict of interest statement

Declaration of competing interest The Authors declare that there is no conflict of interest.

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