019 Investigating OX40L and its role in mediating cutaneous and systemic autoimmune disease

Systemic lupus erythematosus (SLE) is a devastating systemic inflammatory disease, with prominent female bias. Recent literature suggests the OX40/OX40L costimulatory pathway may play an important role in development of SLE. GWAS have identified TNFSF4 (OX40L) as SLE susceptibility locus. OX40L stimulation T cells through OX40 receptor has been shown to promote follicular helper (Tfh) phenotype, and Ox40l knockout demonstrated ameliorate phenotype transgenic induced mouse models. We recently reported model (K5-Vgll3) where epidermal overexpression female-biased transcription cofactor Vgll3 results upregulation epidermis well To address this model, we demonstrate that KO decreased disease severity, consistent being for propagating VGLL3-mediated inflammation. investigate link between VGLL3 expression skin, created N/TERT VGLL3-Myc-DDK cell system. IP-mass spectrometry complexes factor TEAD1, previously bind upstream OX40L, top interactor. Assessing via immunofluorescence single-cell RNA-seq (scRNA-seq), found increased on KCs CD4+ both K5-Vgll3 skin compared controls. ScRNA-seq also showed OX40+ were skewed towards Tfh/T peripheral (Tph) phenotype. Similarly, spatial-seq population Tfh/Tph-like not present healthy Overall, our data indicates cutaneous controls transcriptional regulation required mediate downstream SLE-like inflammation, possibly promoting skin.