MOLECULAR EVENTS IN THE INDUCTION OF A NONRESPONSIVE STATE IN INTERLEUKIN 2-PRODUCING HELPER LYMPHOCYTE-T CLONES
MOLECULAR EVENTS IN THE INDUCTION OF A NONRESPONSIVE STATE IN INTERLEUKIN 2-PRODUCING HELPER LYMPHOCYTE-T CLONES
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DOI：
10.1073/pnas.84.15.5409
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发表时间：
1987-08-01
影响因子：
11.1
通讯作者：
SCHWARTZ, RH
中科院分区：
文献类型：
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作者：
JENKINS, MK;PARDOLL, DM;SCHWARTZ, RH
将正常的产生白细胞介素2（IL-2）的辅助性T细胞克隆暴露于抗原和1-乙基-3-（3-二甲基氨基丙基）二甲酰亚胺处理的抗原呈递细胞，导致对随后的抗原和正常抗原呈递细胞刺激的增殖无反应性。在目前的研究中，我们已经研究了分子事件，伴随着这种无反应状态的诱导。以这种方式刺激的T细胞不能产生IL-2，但是白细胞介素3，干扰素-γ，和IL-2受体被部分诱导，T细胞受体β。mRNA被完全诱导。虽然T细胞反应性与IL-2产生缺陷相关，但在诱导期添加IL-2未能阻止无反应性状态的发展。关键的生化事件似乎是细胞内钙的增加。从培养基中去除钙防止诱导的响应状态，而另外的钙离子载体离子霉素诱导无响应以及所有相关的部分激活事件。因此，在非促有丝分裂条件下细胞内钙的增加似乎启动了另一种激活程序，该程序阻止T细胞响应随后的正常激活信号产生IL-2。讨论了该体外模型在体内耐受诱导中的意义。
Exposure of normal interleukin 2 (IL-2)-producing helper T-cell clones to antigen and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-treated antigen-presenting cells results in proliferative unresponsiveness to subsequent stimulation with antigen and normal antigen-presenting cells. In the present study, we have examined the molecular events that accompany the induction of this unresponsiveness state. T cells stimulated in this manner failed to produce IL-2, but interleukin 3, interferon-.gamma., and IL-2 receptors were partially induced and T-cell receptor .beta. mRNA was fully induced. Although T-cell responsiveness correlated with an IL-2 production defect, addition of IL-2 during the induction phase failed to prevent development of the unresponsiveness state. The critical biochemical event appeared to be an increase in intracellular calcium. Removal of calcium from the medium prevented induction of the responsiveness state, whereas addition of the calcium ionophore ionomycin induced unresponsiveness as well as all of the related partial activation events. Thus, an increase in intracellular calcium under nonmitogenic conditions appears to initiate an alternative activation program that prevents the T cell from producing IL-2 in response to subsequent normal activation signals. The significance of this in vitro model for tolerance induction in vivo is discussed.