Regulation of IFN regulatory factor 4 expression in human T cell leukemia virus-I-transformed T cells

J Immunol. 2002 Sep 15;169(6):3120-30. doi: 10.4049/jimmunol.169.6.3120.

Abstract

IFN regulatory factor (IRF)-4 is a lymphoid/myeloid-restricted member of the IRF transcription factor family that plays an essential role in the homeostasis and function of mature lymphocytes. IRF-4 expression is tightly regulated in resting primary T cells and is transiently induced at the mRNA and protein levels after activation by Ag-mimetic stimuli such as TCR cross-linking or treatment with phorbol ester and calcium ionophore (PMA/ionomycin). However, IRF-4 is constitutively upregulated in human T cell leukemia virus type I (HTLV-I) infected T cells as a direct gene target for the HTLV-I Tax oncoprotein. In this study we demonstrate that chronic IRF-4 expression in HTLV-I-infected T lymphocytes is associated with a leukemic phenotype, and we examine the mechanisms by which continuous production of IRF-4 is achieved in HTLV-I-transformed T cells. IRF-4 expression in HTLV-1-infected cells is driven through activation of the NF-kappaB and NF-AT pathways, resulting in the binding of p50, p65, and c-Rel to the kappaB1 element and p50, c-Rel, and NF-ATp to the CD28RE element within the -617 to -209 region of the IRF-4 promoter. Furthermore, mutation of either the kappaB1 or CD28RE sites blocks Tax-mediated transactivation of the human IRF-4 promoter in T cells. These experiments constitute the first detailed analysis of human IRF-4 transcriptional regulation within the context of HTLV-I infection and transformation of CD4(+) T lymphocytes.

Publication types

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

MeSH terms

  • Base Sequence
  • CD28 Antigens / analysis
  • CD28 Antigens / genetics
  • Cell Transformation, Viral / genetics
  • Cell Transformation, Viral / immunology*
  • DNA-Binding Proteins / analysis
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / biosynthesis*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation / immunology
  • Gene Products, tax / antagonists & inhibitors
  • Gene Products, tax / physiology
  • Human T-lymphotropic virus 1 / immunology*
  • Humans
  • I-kappa B Proteins*
  • Interferon Regulatory Factors
  • Jurkat Cells
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology*
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism
  • NFATC Transcription Factors
  • Nuclear Proteins*
  • Promoter Regions, Genetic / immunology
  • Protein Structure, Tertiary / genetics
  • Response Elements / immunology
  • Sp1 Transcription Factor / analysis
  • Sp1 Transcription Factor / genetics
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism*
  • T-Lymphocyte Subsets / virology
  • Transcription Factors / analysis
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / biosynthesis*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • CD28 Antigens
  • DNA-Binding Proteins
  • Gene Products, tax
  • I kappa B beta protein
  • I-kappa B Proteins
  • Interferon Regulatory Factors
  • NF-kappa B
  • NFATC Transcription Factors
  • Nuclear Proteins
  • Sp1 Transcription Factor
  • Transcription Factors
  • interferon regulatory factor-4