Modiano J F, Mayor J, Ball C, Chitko-McKown C G, Sakata N, Domenico-Hahn J, Lucas J J, Gelfand E W
Department of Pathobiology, Texas A and M University, College Station, Texas.
Cell Immunol. 1999 Oct 10;197(1):19-29. doi: 10.1006/cimm.1999.1563.
Cell growth and proliferation as well as cell cycle arrest and apoptosis all play integral roles in the cellular immune response. The signals that lead to cytokine production by antigen- or mitogen-stimulated T cells have been studied in detail. However, it is not fully understood how these signals promote cell cycle entry and progression to DNA synthesis in T lymphocytes, especially in primary cells. We used a model distinguishing between competence and progression phases to examine quantitative and qualitative differences in signal transduction that resulted in cell cycle entry and G1 phase arrest or led to DNA synthesis in human T cells. Resting peripheral blood T cells were rendered competent by stimulation with submitogenic concentrations of phytohemagglutinin (PHA) or they were stimulated to proliferate using mitogenic concentrations of PHA. The competent state (that is, the capacity to proliferate in response to exogenous IL-2) was characterized by calcium mobilization, a protein kinase C-dependent internalization of CD3, increased mitogen-activated protein kinase (MAPK) activity, transient translocation of AP-1 transcription factors to the nucleus, expression of immediate early genes, activation of G1-phase cyclin-dependent kinases, and increased CD25 (IL-2Ralpha) expression. However, all of these events were of lesser magnitude in T cells rendered competent than in T cells stimulated to proliferate. Furthermore, the mitogenic stimulus induced a different pattern of MAPK activation and sustained translocation of AP-1 to the nucleus with concomitant IL-2 production. The data indicate that quantitative and qualitative differences in early signaling events distinguish the acquisition of the competent state or the induction of cytokine production with a commitment to T-cell proliferation.
细胞生长与增殖以及细胞周期停滞和凋亡在细胞免疫反应中均发挥着不可或缺的作用。抗原或丝裂原刺激的T细胞产生细胞因子的信号已得到详细研究。然而，这些信号如何促进T淋巴细胞尤其是原代细胞进入细胞周期并进展至DNA合成，目前尚未完全明确。我们使用一个区分感受态和进展阶段的模型，来研究导致细胞周期进入、G1期停滞或人类T细胞DNA合成的信号转导中的定量和定性差异。用亚致有丝分裂浓度的植物血凝素（PHA）刺激静息外周血T细胞使其进入感受态，或用致有丝分裂浓度的PHA刺激它们增殖。感受态状态（即对外源性白细胞介素-2作出增殖反应的能力）的特征包括钙动员、蛋白激酶C依赖的CD3内化、丝裂原活化蛋白激酶（MAPK）活性增加、AP-1转录因子向细胞核的短暂易位、立即早期基因的表达、G1期细胞周期蛋白依赖性激酶的激活以及CD25（白细胞介素-2受体α）表达增加。然而，与被刺激增殖的T细胞相比，进入感受态的T细胞中所有这些事件的程度都较小。此外，有丝分裂刺激诱导了不同模式的MAPK激活以及AP-1持续易位至细胞核并伴随白细胞介素-2产生。数据表明，早期信号事件中的定量和定性差异区分了感受态状态的获得或细胞因子产生的诱导以及对T细胞增殖的承诺。
