T cell PKCδ kinase inactivation induces lupus-like autoimmunity in mice

- Impairment in T cell PKCδ in this mouse model is causing deficient ERK signaling, as observed in SLE.
- Decreased T cell PKCδ signaling results in DNA demethylation, overexpression of TNSF7 and LFA1 genes, and autoimmunity.
- Abnormalities in T cell PKCδ deficient transgenic mice resemble human active lupus
- Decreased ERK signaling due to PKCδ inactivation may have a causative role in human lupus

Genetic and environmental factors contribute to the onset and progression of lupus. CD4 + T cells from patients with active lupus show a decreased ERK signaling pathway, which causes changes in gene expression. The defect points to its upstream regulator, PKCδ, which exhibits a deficient activity due to oxidative stress. Our aim was to investigate the effect of a defective PKCδ in the development of lupus.We generated a double transgenic C57BL6 × SJL mouse that expresses a doxycycline-induced dominant negative PKCδ (dnPKCδ) in T cells. The transgenic mice displayed decreased T cell ERK signaling, decreased DNMT1 expression and overexpression of methylation sensitive genes involved in the exaggerated immune response in the pathogenesis of lupus. The mice developed anti-dsDNA autoantibodies and glomerulonephritis with IgG deposition.The study indicates common pathogenic mechanisms with human lupus, suggesting that environmentally-mediated T cell PKCδ inactivation plays a causative role in lupus.