Defective transcription of the IL-2 gene is associated with impaired expression of c-Fos, FosB, and JunB in anergic T helper 1 cells.
Anergic CD4+ Th cells do not produce IL-2 when challenged with Ag-pulsed accessory cells because of a transcriptional defect. In this work, we report that these anergic T cells are defective in their ability to up-regulate protein binding and transactivation at two critical IL-2 DNA enhancer elements: NF-AT (nuclear factor of activated T cells; a sequence that binds a heterotrimeric NFATp, Fos, and Jun protein complex) and Activator Protein-1 (AP-1) (that binds Fos and Jun heterodimers). Western blot analysis of nuclear extracts showed that the impaired DNA-protein interactions in anergic T cells were associated with poor expression of the inducible AP-1 family members c-Fos, FosB, and JunB. However, the reduced expression of these proteins was not the result of a global TCR/CD3-signaling defect because CD3 cross-linking induced an equivalent increase in intracellular-free calcium ions, as well as NFATp dephosphorylation, translocation to the nucleus, and DNA binding in both normal and anergic T cells. Thus, defective IL-2 gene transcription appears to be due, at least in part, to a selective block in the expression of the AP-1 Fos and Jun family members in anergic T cells.
Mondino
A
A
Department of Microbiology, University of Minnesota, Minneapolis 55455, USA.
Whaley
C D
CD
DeSilva
D R
DR
Li
W
W
Jenkins
M K
MK
Mueller
D L
DL
D000818:Animals; D001483:Base Sequence; D001692:Biological Transport / Q000235:genetics / Q000276:immunology; D002118:Calcium / Q000378:metabolism; D017635:Clonal Anergy / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis*; D018417:Th1 Cells / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000276:immunology*
D004268:DNA-Binding Proteins; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D002118:Calcium