Lowering CD40L expression in Murine Lupus Results in an Increase in Disease Indicators in Female but not Male B6 mice

Abstract

Our lab has previously described a mouse model (CD40L{Delta}5) that produces only 60% of WT CD40L due to a targeted deletion in an RNA binding site within the CD40L message. The CD40L{Delta}5 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). Two mouse models of SLE were assessed: The first, termed PIL, used pristane to induce disease over a six-month period and the second utilized a chronic graft-versus-host disease (bm12-cGVHD) that resembles lupus based on multiple parameters and allowed us to monitor the early events in disease development. Importantly, we found that in both model systems female mice expressing the CD40L{Delta}5 mutation showed a consistent increase in elevated antibody secreting cells and autoantibody titers. Also, PIL female CD40L{Delta}5 mice had higher levels of immunocomplex deposition in the kidney compared to all other cohorts. In the bm12-cGVHD model, cellular increases in GC cells along with an altered cytokine profile of donor CD4+ T cells and host dendritic cells (DCs) reflected a significant skewing of CD40L{Delta}5 female CD4 T cells towards a Th2 phenotype. Overall, our results support a more nuanced role for CD40L in lupus than previously described and suggest a sex-determined threshold of CD40L-CD40 signaling that demarcates an interface between protection and exacerbation at the very early steps of disease progression.