Direct activation of human resting T cells by IL 2: the role of an IL 2 receptor distinct from the Tac protein.
Direct activation of human resting T cells by IL 2: the role of an IL 2 receptor distinct from the Tac protein.
复制标题
IL 2 直接激活人类静息 T 细胞：不同于 Tac 蛋白的 IL 2 受体的作用。
作者：
L. Bich;M. Dukovich;N. Peffer;A. Fauci;J. Kehrl;W. Greene
高浓度的白细胞介素2（IL 2）被证明在明显缺乏其他激活信号的情况下产生延迟但明显的纯化的静息T细胞增殖。由于IL 2的这些刺激作用发生在没有可检测的Tac+细胞的情况下，因此研究了IL 2最初可能与不同于Tac蛋白的IL 2结合蛋白相互作用的可能性。用125 I-IL 2进行的化学交联研究揭示了这些未受刺激的T细胞表面上存在与Tac蛋白不同的IL 2结合蛋白。该第二种IL 2受体的分子大小估计为70，000道尔顿，与抗Tac抗体缺乏反应性，并且似乎与最近提出的作为高亲和力IL 2受体组分的p70蛋白相同。对未活化T细胞进行的IL 2结合试验的Scatchard分析显示每个细胞约有600至700个p70位点，表观Kd为340 pM。这些数据表明，静息T细胞上存在的p70蛋白结合IL 2的亲和力与以前公认的高和低亲和力形式的受体相比，中等，并可能占高浓度的IL 2诱导静息T细胞增殖所需的。为了研究IL 2与p70蛋白结合的早期生物学后果，检测了参与T细胞活化的基因表达的潜在变化。北方印迹显示，在用高浓度IL 2刺激静息T细胞后，c-myc、c-myb和Tac mRNA的快速诱导。抗Tac抗体不抑制IL 2诱导的这些基因的表达，表明p70蛋白而不是Tac抗原或高亲和力IL 2受体复合物介导了该信号。然而，与这些早期活化事件相反，抗Tac抗体显著抑制IL 2诱导的T细胞增殖。这一发现暗示了IL 2受体的高亲和力形式在IL 2活化的T细胞的增殖反应中。因此，这些数据支持高剂量IL 2诱导静息T细胞增殖的两步模型，包括通过p70蛋白初始产生活化或“感受态”信号，以及通过高亲和力形式的受体随后产生增殖或“进展”信号。
High concentrations of interleukin 2 (IL 2) were shown to produce a delayed but pronounced proliferation of purified resting T cells in the apparent absence of other activation signals. Because these stimulatory effects of IL 2 occurred in the absence of detectable Tac+ cells, the possibility that IL 2 might be initially interacting with an IL 2 binding protein distinct from the Tac protein was studied. Chemical cross-linking studies with 125I-IL 2 revealed the presence of an IL 2 binding protein distinct from the Tac protein on the surface of these unstimulated T cells. This second IL 2 receptor has an estimated molecular size of 70,000 daltons, lacks reactivity with the anti-Tac antibody, and appears to be identical to the p70 protein recently proposed as a component of the high affinity IL 2 receptor. Scatchard analysis of IL 2 binding assays performed with the unactivated T cells revealed approximately 600 to 700 p70 sites per cell and an apparent Kd of 340 pM. These data indicate that the p70 protein present on resting T cells binds IL 2 with an intermediate affinity compared with the previously recognized high and low affinity forms of the receptor and may account for the high concentration of IL 2 needed to induce resting T cell proliferation. To investigate the early biologic consequences of IL 2 binding to the p70 protein, potential changes in the expression of genes involved in T cell activation were examined. Northern blotting revealed the rapid induction of c-myc, c-myb, and Tac mRNA after stimulation of resting T cells with a high concentration of IL 2. The anti-Tac antibody did not inhibit IL 2 induced expression of these genes, suggesting that the p70 protein rather than the Tac antigen or the high affinity IL 2 receptor complex mediated this signal. However, in contrast to these early activation events, the anti-Tac antibody significantly inhibited IL 2 induced T cell proliferation. This finding implicates the high affinity form of the IL 2 receptor in the proliferative response of the IL 2 activated T cells. Thus these data support a two step model for the induction of resting T cell proliferation by high doses of IL 2 involving the initial generation of an activation or "competence" signal through the p70 protein and a subsequent proliferation or "progression" signal through the high affinity form of the receptor.