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Chronic TLR7 activation promotes expansion of activated CD11c+ double-negative B cells and autoreactive humoral responses in lupus-like autoimmunity
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DOI：10.3389/fimmu.2026.1920764.png)
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Abstract
En 中文
Age-associated B cells (ABCs) have emerged as a distinct B cell population associated with aging; chronic inflammation; and autoimmunity. Notably; the expansion of ABC-like CD11c-expressing B cells has been observed in patients with systemic lupus erythematosus and in experimental models of lupus-like disease; suggesting their potential involvement in disease pathogenesis. Although their relevance in autoimmunity is increasingly appreciated; the identity and functional contribution of CD11c+ B cell populations arising during chronic Toll-like receptor 7 (TLR7)-driven immune activation remain incompletely defined. In this study; we investigated the role of CD11c+CD21–CD23– B cells (hereafter DN CD11c+ B cells) in a lupus-like model induced by chronic activation of TLR7. Young female C57BL/6 mice were treated with the TLR7 agonist imiquimod for 10 weeks; leading to systemic immune activation characterized by splenomegaly; elevated proinflammatory cytokines; anti-nuclear autoantibodies; and early renal alterations. This was accompanied by a marked remodeling of the B cell compartment; including expansion of non-canonical subsets; particularly DN CD11c+ B cells. Phenotypic analysis revealed that DN CD11c+ B cells exhibited an activated profile; with increased expression of T-bet; TLR7; costimulatory molecules; and activation-associated markers; as well as a higher proportion of class-switched cells. Functional assays demonstrated that DN CD11c+ B cells from imiquimod-treated mice were hyperresponsive to TLR7 stimulation. Furthermore; DN CD11c+ B cells were a major ex vivo source of autoreactive antibodies; including IgG directed against nuclear antigens; whereas conventional B cell subsets showed minimal contribution. In addition; DN CD11c+ B cells were detected in renal tissue prior to the development of overt pathology; suggesting a role in early tissue infiltration. Importantly; pharmacological activation of the adenosine A2A receptor preferentially reduced the frequency of DN CD11c+ B cells; autoantibody production; and immune cell infiltration; while largely sparing conventional B cell subsets. Collectively; these findings identify expanded and activated DN CD11c+ B cells as important effectors linking chronic innate immune activation to autoreactive humoral responses and highlight A2A receptor signaling as a potential strategy to selectively modulate pathogenic B cell responses in lupus-like autoimmunity.
Keywords:
autoantibodies
lupus
imiquimod
TLR7
ADORA2A
ABC-like
DN CD11c+ B cells
extrafollicular response
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