Labuda T, Sundstedt A, Dohlsten M
BMC Immunobiology, Department of Tumor Immunology, University of Lund, Sölvegatan 21, 223 62 Lund, Sweden.
Int Immunol. 2000 Mar;12(3):253-61. doi: 10.1093/intimm/12.3.253.
We have recently described the novel A6H antigen expressed on human peripheral blood T cells and on renal cell carcinoma cells. Cross-linking of the A6H antigen results in co-stimulation of human CD4(+) T cells, characterized by induction of the transcription factor activator protein-1 (AP-1), proliferation and prominent IFN-gamma production, but low levels of IL-2. The proximal signaling events associated with A6H ligation include protein tyrosine kinase phosphorylation and association of p56 Lck, ZAP-70 and the TCR zeta chain. In this study we show that A6H co-stimulation selectively induced activation of the p38 mitogen-activated protein kinase (MAPK) pathway, whereas no significant c-Jun N-terminal kinases (JNK) activity was observed. In contrast, CD28 co-stimulation resulted in both p38 and JNK MAPK activities. Human CD4(+) T cells co-stimulated with A6H up-regulated AP-1 binding proteins reactive with a proximal AP-1 binding site in the human IFN-gamma promoter and a consensus AP-1 binding site. Moreover, preincubation of the T cells with the specific p38 MAPK inhibitor SB203580 resulted in decreased AP-1 binding following A6H or CD28 co-stimulation. This suggests that the p38 MAPK pathway is required for induction of full AP-1 binding activity in human CD4(+) T cells co-stimulated with A6H or CD28. Blocking the p38 MAPK pathway by SB203580 completely inhibited IFN-gamma production from A6H co-stimulated T cells and radically reduced IFN-gamma production from T cells co-stimulated with anti-CD28. In contrast, no significant inhibition of IL-2 production was seen after blocking of the p38 MAPK in either A6H or CD28 co-stimulated T cells. Since the p38 MAPK recently has been shown to be critically involved in regulation of IFN-gamma production from T(h)1 cells, we propose that A6H co-stimulation induces a specific pathway, mediated via p38 and AP-1 activation, for induction of a T(h)1 profile in human CD4(+) T cells.
我们最近描述了一种在人外周血T细胞和肾癌细胞上表达的新型A6H抗原。A6H抗原的交联导致人CD4(+) T细胞的共刺激，其特征在于转录因子激活蛋白-1（AP-1）的诱导、增殖和显著的IFN-γ产生，但IL-2水平较低。与A6H连接相关的近端信号事件包括蛋白酪氨酸激酶磷酸化以及p56 Lck、ZAP-70和TCR ζ链的结合。在本研究中，我们表明A6H共刺激选择性地诱导p38丝裂原活化蛋白激酶（MAPK）途径的激活，而未观察到明显的c-Jun N端激酶（JNK）活性。相比之下，CD28共刺激导致p38和JNK MAPK活性。与A6H共刺激的人CD4(+) T细胞上调了与人类IFN-γ启动子中的近端AP-1结合位点和共有AP-1结合位点反应的AP-1结合蛋白。此外，用特异性p38 MAPK抑制剂SB203580对T细胞进行预孵育导致A6H或CD28共刺激后AP-1结合减少。这表明p38 MAPK途径是在与A6H或CD28共刺激的人CD4(+) T细胞中诱导完全AP-1结合活性所必需的。用SB203580阻断p38 MAPK途径完全抑制了A6H共刺激的T细胞产生的IFN-γ，并从根本上降低了抗CD28共刺激T细胞产生的IFN-γ。相比之下，在A6H或CD28共刺激的T细胞中阻断p38 MAPK后，未观察到对IL-2产生的显著抑制。由于最近已证明p38 MAPK在调节Th1细胞产生IFN-γ中起关键作用，我们提出A6H共刺激诱导了一条通过p38和AP-1激活介导的特异性途径，用于在人CD4(+) T细胞中诱导Th1型。
