E4BP4 overexpression: a protective mechanism in CD4+ T cells from SLE patients

J Autoimmun. 2013 Mar;41:152-60. doi: 10.1016/j.jaut.2013.01.004. Epub 2013 Jan 20.


Systemic lupus erythematosus (SLE) is a prototype autoimmune disease characterized by various immunological abnormalities, including dysregulated activation of T and B lymphocytes, which trigger autoantibody production and immune-complex deposition. E4BP4, also known as NFIL3, has emerged as a major transcription factor that regulates the development and function of immune cells in a number of lineages. E4BP4 has been shown to regulate cytokines expression, and its synthesis is in turn controlled by various cytokines. To date, the roles of E4BP4 in immune dysregulation and autoimmune disorders are unclear. In this study, we demonstrated that E4BP4 expression is increased in CD4(+) T cells isolated from patients with active systemic lupus erythematosus (SLE), especially in patients treated with glucocorticoid (GC). Increased expression of E4BP4 inhibited the activation and self-reactivity of T cells stimulated by anti-CD3/CD28 antibodies. In contrast, the self-reactivity was enhanced in CD4(+) T cells from SLE patients following E4BP4 gene silencing and the production of autoantibody was increased in autologous B cells. We further demonstrated that E4BP4 directly regulated CD40L expression by binding to the promoter region and altering histone acetylation and methylation of the CD40L loci. Taken together, our data provide evidence that E4BP4 can inhibit CD40L expression through epigenetic modifications in the promoter region of CD40L, thus negatively regulating self-reactivity of SLE CD4(+) T cells. Furthermore, our data demonstrate that overexpression of E4BP4 initiates a protective mechanism in SLE CD4(+) T cells, which may be a promising target in the therapy for SLE.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antibodies / immunology
  • Antibodies / pharmacology
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / immunology*
  • Basic-Leucine Zipper Transcription Factors / metabolism
  • Blotting, Western
  • CD28 Antigens / immunology
  • CD3 Complex / immunology
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • CD40 Ligand / genetics
  • CD40 Ligand / immunology
  • CD40 Ligand / metabolism
  • Cells, Cultured
  • Female
  • Flow Cytometry
  • Gene Expression / immunology*
  • Glucocorticoids / therapeutic use
  • Histones / metabolism
  • Humans
  • Lupus Erythematosus, Systemic / drug therapy
  • Lupus Erythematosus, Systemic / immunology*
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Male
  • Middle Aged
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Young Adult


  • Antibodies
  • Basic-Leucine Zipper Transcription Factors
  • CD28 Antigens
  • CD3 Complex
  • Glucocorticoids
  • Histones
  • NFIL3 protein, human
  • CD40 Ligand