Lowering CD40L expression in murine lupus results in an increase in disease indicators in female but not male B6 mice.

Our laboratory has previously described a mouse model (CD40LΔ5) that produces 60% of wild-type CD40L due to a targeted deletion in an RNA binding site within the CD40L message. The CD40LΔ5 mutation, which destabilizes CD40L mRNA during T-cell activation, causes disrupted germinal center (GC) formation, leading to reduced levels of memory B cells and switched antibodies. In this study, we used our model of limited CD40L expression to investigate its effect on systemic lupus erythematosus (SLE, or lupus) using 2 different mouse models of SLE. The first model used the hydrocarbon oil pristane to induce lupus-like symptoms over a 6-month period, and the second utilized a chronic graft-versus-host disease (bm12-cGVHD) that resembles lupus and allowed us to monitor the early events in disease development. Importantly, we found that in both systems, female mice expressing the CD40LΔ5 mutation showed a consistent increase in elevated antibody-secreting cells and autoantibody titers. In addition, pristane-induced lupus female CD40LΔ5 mice had higher levels of immunocomplex deposition in the kidney compared to all other cohorts. Increases in autoantibodies and GC cells in female CD40LΔ5 versus wild-type recipient mice were also evident in the bm12-cGVHD model. Additionally, CD4+ T cells from female CD40LΔ5 recipient mice were skewed toward a Th2 phenotype and expressed a distinct cytokine expression pattern upon activation of dendritic cells. Overall, our results support a nuanced role for optimal CD40L expression in lupus and suggest a sex-determined threshold of CD40L-CD40 signaling that is critical at the very early steps of disease progression.