IONIC CONDUCTANCES AND CD4 LYMPHOCYTE DIFFERENTIATION

离子电导和 CD4 淋巴细胞分化

• 批准号: 2672750
• 负责人: BRUCE D FREEDMAN
• 金额: $ 20.23万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2672750
• 关键词: T cell receptor; calcium channel; calcium flux; cell differentiation; cytochrome c; genetically modified animals; helper T lymphocyte; laboratory mouse; leukocyte activation /transformation; potassium channel; single cell analysis; tissue /cell culture

Antigen-mediated calcium signaling is a critical determinant of lymphocyte gene expression and has been associated with functional responses to T-cell receptor (TCR) stimulation including proliferation, anergy, apoptosis and memory. Because the outcome to stimulation of naive cells is not predetermined, elements that regulate the calcium response, have the capacity to regulate peripheral T cell differentiation in vivo. We have identified profound modulation in the expression of voltage- dependent (Kv) channels that correlates with each functional response to antigen in vivo. Kv channels have been previously shown to regulate calcium signaling in vitro. The unique Kv channel phenotypes of each subpopulation of differentiating T cells has led us to hypothesize that Kv channels may be important determinants of the calcium responses and the function of differentiating lymphocytes. T cell differentiation, therefore may be controlled by the unique balance between antigen and receptor, the constituents in the immune microenvironment, which regulated Kv channel activity, and also upon the repertoire of Kv channels expressed by an individual cell. Any shift in the balance of these factors could affect the membrane potassium permeability, shift the electrical potential across the lymphocyte membrane, alter calcium signaling, and the cells capacity to produce and secrete cytokines, respond to external factors, express cell surface molecules, and differentiated. If calcium does direct alternative functional responses of T cells, it is unlikely to result from simple changes in its steady-state concentration. Rather, the outcome to stimulation is more likely to be encoded in features such as the latency, duration and frequency of calcium oscillations. Kv channels help to define the frequency and duration of calcium oscillations to the extent that changes in the potassium permeation of Kv channels result in parallel changes in the membrane potential, and calcium concentration within mitogen stimulated human lymphocytes. It is not known, however whether antigen- mediated calcium signaling is regulated differently at each stage of T cell differentiation, or if voltage-dependent potassium channels regulate calcium signaling in vivo. Although potassium channels are not the sole determinants of calcium oscillations, given the role of potassium channels in setting the membrane potential and the dependence of calcium influx in the membrane electrical potential difference, modulation of potassium channel expression and permeation, would likely have a significant impact upon calcium signaling and T cell functions in vivo. The central hypothesis of this proposal is that the TCR-mediated calcium response regulates CD4plus lymphocyte differentiation, and that Kv channel regulate the secondary responses of differentiated cells to antigen.

抗原介导的钙信号是一个关键的决定因素 淋巴细胞基因的表达，并与 对T细胞受体(TCR)刺激的功能反应包括 增殖、无能、凋亡和记忆。因为 刺激幼稚细胞的结果并不是预先确定的， 调节钙反应的元素有能力 体内调节外周T细胞分化。我们有 在电压表达中发现了深刻的调制- 与每个功能相关的依赖(Kv)通道 体内对抗原的反应。KV频道之前已经 在体外显示可以调节钙信号。独一无二的Kv 分化T细胞各亚群的通道表型 让我们假设Kv频道可能很重要 钙反应的决定因素和钙离子的作用 正在分化的淋巴细胞。T细胞分化，因此可能 受抗原和受体之间独特的平衡所控制， 免疫微环境中的成分，调节 KV通道活动，以及KV通道的曲目 由单个细胞表达的。这些平衡的任何变化 影响膜钾通透性、漂移的因素 跨越淋巴细胞膜的电势，改变 钙信号和细胞产生和分泌的能力 细胞因子，对外界因素做出反应，表达细胞表面 分子，并分化。如果钙确实直接替代了 T细胞的功能反应，不太可能由简单的 其稳态浓度的变化。相反，结果是 刺激更有可能编码在诸如 钙振荡的潜伏期、持续时间和频率。KV 经络有助于确定钙的频率和持续时间 振荡到钾渗透变化的程度 Kv通道的变化导致膜的平行变化 刺激的有丝分裂原内的电位和钙浓度 人类淋巴细胞。然而，目前尚不清楚抗原- 介导的钙信号在不同的阶段受到不同的调节 T细胞分化，或电压依赖性钾通道 调节体内的钙信号。虽然钾离子通道 不是钙振荡的唯一决定因素，考虑到 钾通道在膜电位和膜电位调节中的作用 膜电学中钙离子内流的依赖性 电位差、钾通道表达的调控 和渗透性，可能会对 钙信号和T细胞在体内发挥作用。中环 这一建议的假设是TCR介导的钙 反应调节CD4+淋巴细胞分化， KV通道调节分化细胞的次级反应 与抗原有关。