Differential induction of the NF-AT complex during restimulation and the induction of T-cell anergy.
Stimulation of human CD4+ T-cell clones through the T-cell receptor (TcR) by high doses of specific peptide results in the induction of a long-lived state of nonresponsiveness that has been called anergy. During the induction of anergy, T cells are phenotypically similar to cells responding to an immunogenic stimulus. The amount of TcR at the cell surface is downmodulated, whereas the CD2 and CD25 receptors are increased. When restimulated, however, anergic T cells fail to up-regulate transcription of the IL-2 gene and in consequence do not produce IL-2. In this study, we have compared the ability of various transcription factors to bind to their appropriate site on DNA. Factors were isolated from the nuclei of T cells that were in the induction phase of anergy or were undergoing activation. The pattern of binding activity in restimulated T cells is consistent with the pattern that has previously been shown to regulate T-cell-specific expression of the IL-2 and the beta chain of the TcR genes. The measured binding to a TCF-1 site is the same in the nuclei of resting, activated, and anergized cells. The inducible factors NK-kappa B, beta E2, CD28RC, and AP-1 are not expressed in resting cells and are twofold lower in anergized as compared with activated cells. In contrast, anergic T cells express approximately eightfold lower amounts of NF-AT, a member of the class of inducible factors that regulates IL-2 gene transcription.(ABSTRACT TRUNCATED AT 250 WORDS)
Wotton
D
D
Department of Immunology, St. Mary's Hospital Medical School, Imperial College of Science, Technology and Medicine, London, England.
Higgins
J A
JA
O'Hehir
R E
RE
Lamb
J R
JR
Lake
R A
RA
D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002118:Calcium / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D017635:Clonal Anergy / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D004586:Electrophoresis / Q000379:methods; D005434:Flow Cytometry; D006389:Hemagglutinins, Viral / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping / Q000379:methods; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology*; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D009975:Orthomyxoviridae / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D014157:Transcription Factors / Q000096:biosynthesis*; D014158:Transcription, Genetic / Q000235:genetics
D004268:DNA-Binding Proteins; D006389:Hemagglutinins, Viral; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D014157:Transcription Factors; D002118:Calcium