IONIC CONDUCTANCES AND CD4 LYMPHOCYTE DIFFERENTIATION

离子电导和 CD4 淋巴细胞分化

• 批准号: 2406164
• 负责人: BRUCE D FREEDMAN
• 金额: $ 19.58万
• 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/2406164
• 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.

抗原介导的钙信号传导是一个关键的决定因素， 淋巴细胞基因表达，并已与 对T细胞受体（TCR）刺激的功能反应，包括 增殖、无反应性、凋亡和记忆。 因为 刺激幼稚细胞的结果不是预先确定的， 调节钙反应的元素，有能力 在体内调节外周T细胞分化。 我们有 在电压的表达中发现了深刻的调制- 依赖性（Kv）通道，其与每个功能相关 体内对抗原的反应。 Kv频道以前 显示其在体外调节钙信号传导。 独特的KV 每个分化T细胞亚群的通道表型 让我们假设千伏通道可能是重要的 钙反应的决定因素和 分化淋巴细胞。 因此，T细胞分化可能 由抗原和受体之间的独特平衡控制， 免疫微环境中的成分， Kv频道活动，以及Kv频道的曲目 由单个细胞表达。 这些平衡的任何变化 影响膜透性、钾迁移的因素 穿过淋巴细胞膜的电位， 钙信号，以及细胞产生和分泌 细胞因子，响应外界因素，表达于细胞表面 分子和分化。 如果钙不直接替代 T细胞的功能反应，它不太可能是由简单的 其稳态浓度的变化。 相反， 刺激更可能被编码在特征中，例如 钙振荡的潜伏期、持续时间和频率。 kV 通道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通道导致膜中的平行变化 电位和促分裂原内的钙浓度 人类淋巴细胞目前尚不清楚，是否抗原- 介导的钙信号传导在每个阶段的调节不同， T细胞分化，或者电压依赖性钾通道 调节体内钙信号传导。 虽然钾离子通道 不是钙波动的唯一决定因素， 钾通道在设置膜电位中的作用 钙离子内流对细胞膜电位的依赖性 电位差，钾通道表达调控 和渗透，可能会有重大影响， 钙信号传导和体内T细胞功能。中央 这一建议的假设是，TCR介导的钙 反应调节CD 4+淋巴细胞分化， Kv通道调节分化细胞的次级反应 抗原。