Shannon M F, Himes S R, Coles L S
Division of Human Immunology, Hanson Centre for Cancer Research, Institute of Medical and Veterinary Science, Adelaide, South Australia.
J Leukoc Biol. 1995 May;57(5):767-73. doi: 10.1002/jlb.57.5.767.
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 IL-4 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-kappa B 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-kappa B binding to this region. However, other transcription factors or coactivators of NF-kappa B 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.
与抗原呈递细胞表面的主要组织相容性复合体I类或II类分子复合的抗原，与T细胞表面的T细胞受体（TCR）相互作用并启动激活级联反应。由抗原呈递细胞产生的其他细胞表面相互作用或可溶性细胞因子介导的所谓共刺激信号，也是T细胞完全激活所必需的。T细胞中高水平的细胞因子基因表达也需要TCR和共刺激信号。粒细胞-巨噬细胞集落刺激因子需要启动子中的序列以及位于上游3kb处的一个强大增强子来响应类似TCR的信号。这些启动子和增强子区域主要由活化T细胞核因子（NFAT）转录因子激活。TCR信号对NFAT的激活在T细胞中白细胞介素-2（IL-2）和IL-4基因转录方面已有充分描述。共刺激信号，如T细胞上CD28细胞表面分子的激活，通过粒细胞-巨噬细胞集落刺激因子（GM-CSF）启动子的一个不同区域导致激活。该区域称为CK-1或CD28反应元件（CD28RE），似乎结合转录因子NF-κB家族的特定成员。人类1型T淋巴细胞白血病病毒（HTLV-1）感染T细胞并可导致GM-CSF表达增加。我们发现HTLV-1反式激活蛋白tax作为GM-CSF和IL-2基因转录的共刺激信号起作用，因为它可以与TCR信号协同介导高水平基因表达。Tax通过CK-1/CD28RE区域激活GM-CSF启动子，也激活NF-κB与该区域的结合。然而，Tax激活还需要其他转录因子或NF-κB的共激活因子，但这些仍有待确定。GM-CSF的CK-1/CD28RE与IL-2 CD28RE高度相似，IL-3基因也包含一个相关区域。这一观察结果，连同GM-CSF和IL-2都通过NFAT对TCR信号作出反应这一事实，意味着T细胞中细胞因子基因表达调控具有高度保守性。
