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

Clin Immunol. 2015 Jun;158(2):193-203. doi: 10.1016/j.clim.2015.03.017. Epub 2015 Mar 28.


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.

Keywords: Autoimmunity; Extracellular signal-regulated kinase (ERK); Lupus; PKCδ; T cells; Transgenic mouse model.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Autoantibodies / metabolism
  • Autoimmunity
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • Doxycycline / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression Regulation, Enzymologic / immunology*
  • Glomerulonephritis / metabolism
  • Immunoglobulin G / metabolism
  • Lupus Erythematosus, Systemic / immunology*
  • Mice
  • Mice, Transgenic
  • Mutation
  • Phosphorylation
  • Promoter Regions, Genetic
  • Protein Kinase C-delta / genetics
  • Protein Kinase C-delta / metabolism*
  • Specific Pathogen-Free Organisms
  • T-Lymphocytes / enzymology*
  • Trans-Activators


  • Anti-Bacterial Agents
  • Autoantibodies
  • Immunoglobulin G
  • Trans-Activators
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases
  • DNMT1 protein, human
  • Dnmt1 protein, mouse
  • Protein Kinase C-delta
  • Extracellular Signal-Regulated MAP Kinases
  • Doxycycline