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GM‐CSF and IL‐2 share common control mechanisms in response to costimulatory signals in T cells
Author(s) -
Shan M. Frances,
Himes S. Roy,
Coles Leeanne S.
Publication year - 1995
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.57.5.767
Subject(s) - biology , immunology , microbiology and biotechnology , immune system , signal transduction , neuroscience
Antigen complexed with major histocompatibility complex class I or II molecules on the surface of antigen presenting cells interacts with the T cell receptor (TCR) on the surface of T cells and initiates an activation cascade. So called costimulatory signals, mediated by other cell surface interactions or soluble cytokines produced by antigen presenting cells, are also required for complete T cell activation. High levels of cytokine gene expression in T cells also required both TCR and costimulatory signals. The granulocyte‐macrophage colony‐stimulating factor requires sequences in the promoter as well as a powerful enhancer located 3kb upstream to respond to TCR‐like signals. These promoter and enhancer regions are mainly activated by the transcription factor nuclear factor of activated T cells (NFAT). The activation of NFAT by TCR signals has been well described for interleukin‐2 (IL‐2) and IL4 gene transcription in T cells. Costimulatory signals, such as activation of the CD28 cell surface molecule on T cells, lead to activation through a distinct region of the granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) promoter. This region is termed the CK‐1 or CD28RE and appears to bind specific members of the NF‐κB family of transcription factors. Human T leukemia virus type 1 (HTLV‐1) infects T cells and can lead to increase GM‐CSF expression. We have found that the HTLV‐1 transactivator protein, tax, acts as a costimulatory signal for GM‐CSF and IL‐2 gene transcription, in that it can cooperate with TCR signals to mediate high level gene expression. Tax activates the GM‐CSF promoter through the CK‐1/CD28RE region and also activates nuclear factor‐κB binding to this region. However, other transcription factors or coactivators of NF‐κB are required for tax activation but these remain to be identified. The CK‐1/CD28RE of GM‐CSF shows a high degree of similarity to the IL‐2 CD28RE and the IL‐3 gene also contains a related region. This observation, together with the fact that both GM‐CSF and IL‐2 respond to TCR signals via NFAT, implies a high degree of conservation in the regulation of cytokine gene expression in T cells. J. Leukoc. Biol . 57: 767‐773; 1995.