Regulation of Fas-mediated immune homeostasis by an activation-induced protein, Cyclon

Blood. 2009 Aug 13;114(7):1355-65. doi: 10.1182/blood-2008-11-189118. Epub 2009 Jun 15.

Abstract

Activation-induced cell death (AICD) plays an essential role in the contraction of activated T cells after eradication of pathogen. Fas (APO-1/CD95) is one of the key cell surface proteins that mediate AICD in CD4(+) and CD8(+) T cells. Despite its prime importance in cell death, regulation of Fas expression in T cells is poorly understood. Here we show that Cyclon, a newly identified cytokine-inducible protein, is induced in T cells on T-cell receptor ligation and important for immune homeostasis. Transgenic expression of Cyclon ameliorated autoimmune phenotype in mice lacking subunits of IL-2R. Transgenic expression of Cyclon markedly enhanced AICD through increased expression of Fas whose expression is essential for Cyclon action. Finally, we demonstrated that activated but not resting CD4(+) T cells with targeted deletion of a Cyclon allele show reduced AICD and expression of Fas, indicating a critical role of Cyclon in Fas expression in activated T cells. We think that our data provide insight into expression regulation of Fas in T cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Death / genetics
  • Cell Death / immunology
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / immunology*
  • Gene Knockdown Techniques
  • Homeostasis / genetics
  • Homeostasis / immunology*
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology*
  • Mice
  • Mice, Knockout
  • Nuclear Proteins / genetics
  • Nuclear Proteins / immunology*
  • Nuclear Proteins / metabolism
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, Interleukin-2 / genetics
  • Receptors, Interleukin-2 / immunology
  • Receptors, Interleukin-2 / metabolism
  • fas Receptor / biosynthesis
  • fas Receptor / genetics
  • fas Receptor / immunology*

Substances

  • Fas protein, mouse
  • Nuclear Proteins
  • Receptors, Antigen, T-Cell
  • Receptors, Interleukin-2
  • cyclon protein, mouse
  • fas Receptor