Nicotine Regulation of T Cell Development

描述（由申请人提供）：有证据表明免疫系统与同样复杂和重要的神经系统之间存在串扰。免疫系统状态显然受到神经系统状态的影响，反之亦然。 该项目参与者的研究增加了一个不断发展的文献，表明天然化学神经递质乙酰胆碱（ACh）和烟草生物碱尼古丁对免疫系统发育和功能具有生理相关影响。烟碱型乙酰胆碱受体（nAChR）家族是乙酰胆碱和尼古丁信号转导的靶点。该项目参与者的研究表明，免疫系统细胞表达特定的nAChR亚型，这表明这些nAChR介导ACh和尼古丁对免疫系统发育和功能的影响。 基于这些发现，这个多研究者项目将测试尼古丁和相关配体可以调节免疫系统发育和功能的中心假设。该项目将确定烟碱配体对与免疫系统功能和发育相关的几个重要参数的影响，特别关注T细胞成熟。该项目的工作还将识别和表征已知和/或潜在的新型nAChR。人类和小鼠的免疫系统成分和胸腺器官培养物将用于表征尼古丁药物暴露对表型不同的T细胞亚群的数量和比例及其阳性/阴性选择标记物表达的影响。其他研究将确定免疫系统nAChR亚基和亚型以及表达它们的细胞亚群，并参考发育和药物治疗效果。将使用器官或细胞培养样本进行细胞因子产生和细胞因子或重组酶激活基因表达的试验，以确定尼古丁和相关化合物影响免疫细胞发育的机制。要解决的假设包括：I）尼古丁调节胸腺中T细胞的发育。2)特异性烟碱配体阻断或模拟烟碱的作用，并揭示ACh对T细胞发育的内源性信号传导的影响。3)参与免疫系统发育的nAChR由T细胞及其祖细胞和/或胸腺基质细胞以发育相关模式表达。4)免疫系统nAChR通过改变细胞因子的表达和/或分泌和/或通过改变参与T细胞受体重排的基因的表达来介导其对T细胞发育的作用。该项目的生物医学相关假设之一是烟草使用和尼古丁暴露影响免疫系统发育。

DESCRIPTION (provided by applicant): There is evidence for cross talk between the immune system and the equally complex and important nervous system. Immune system status is clearly influenced by status of the nervous system, and the opposite is also true. Studies by participants in this project have added to an evolving literature suggesting that the natural chemical neurotransmitter, acetylcholine (ACh), and the tobacco alkaloid, nicotine, have physiologically-relevant effects on immune system development and function. The diverse family of nicotinic acetylcholine receptors (nAChR) are targets for ACh and nicotine signaling. Studies by participants in this project indicate that specific nAChR subtypes are expressed by cells of the immune system, suggesting that these nAChR mediate effects of ACh and nicotine on immune system development and function. Based on these findings, this multi-investigator project will test the central hypothesis that nicotine and related ligands can regulate immune system development and function. The project will establish effects of nicotinic ligands on several important parameters relating to immune system function and development with a particular focus on T cell maturation. Work in the project will also identify and characterize known and/or potentially novel nAChR. Immune system components and thymic organ cultures from humans and mice will be used to characterize effects of nicotinic drug exposures on numbers and proportions of phenotypically-distinct T cell subsets and their expression of markers for positive/negative selection. Other studies will identify immune system nAChR subunits and subtypes and the cell subsets that express them with reference to developmental and drug treatment effects. Assays for cytokine production and for cytokine or recombinase activating gene expression using organ or cell culture samples will be conducted to identify mechanisms by which nicotine and related compounds affect immune cell development. Hypotheses to be addressed include: I) Nicotine regulates the development of T cells in the thymus. 2) Specific nicotinic ligands block or mimic nicotine's effects and reveal influences of endogenous signaling by ACh on T cell development. 3) nAChR involved in immune system development are expressed by T cells and their progenitors and/or by thymic stromal cells in developmentally-relevant patterns. 4) Immune system nAChR mediate their effects on T cell development by altering expression and/or secretion of cytokines and/or by altering expression of genes involved in T cell receptor rearrangements. One of the biomedically-relevant hypotheses of this project is that tobacco use and nicotine exposure affect immune system development.