The Role of The T Cell In The Genesis of Hypertension

描述（由申请人提供）：在过去的几年里，我们实验室和其他实验室的研究表明，先天性和适应性免疫在高血压的发生中起着关键作用。该项目的主要假设是，中枢神经系统协调T细胞、巨噬细胞和树突状细胞的活动，这些细胞反过来影响血管系统和肾脏，从而升高血压。在过去的资助周期中的研究表明，血管紧张素II对室周器官（CVO），特别是穹窿下器官（SFO）的作用激活T细胞并使这些细胞进入肾脏和脉管系统，在那里它们促进血管重塑、血管收缩、盐和容量保留并最终升高血压。我们最近发现，CD 8 + T细胞在对血管紧张素II和DOCA-盐攻击的初始（前2周）反应中具有主导作用，并且缺乏这些细胞的小鼠显示对血管紧张素II的高血压反应迟钝，并且不保留对血管紧张素II的钠和容量。我们提出，交感神经刺激，作用于肾脏或次级淋巴器官激活树突状细胞（DC），部分通过刺激DC产生活性氧（ROS）的生产。通过使用cre-lox技术删除SFO中的p22 phox，我们将阻止血管紧张素II的中枢作用，并且通过删除SFO中的SOD 3，将相反地增强血管紧张素II的中枢作用。这些干预措施将确定血管紧张素II对SFO的作用是否对DC和肾CD 8 + T细胞活化至关重要。我们还将通过选择性肾脏去神经支配检查DC激活主要发生在脾脏还是肾脏。初步数据表明，血管紧张素II增加DC超氧化物产生6倍，主要是通过基于Nox 2的NADPH氧化酶。在目标2中，我们将确定血管紧张素II的中枢作用是否促进DC ROS产生，并进行研究以确定这如何促进CD 8 + T细胞活化。骨髓移植的Nox 2-/-细胞将提供有关DC Nox 2在高血压中的作用的信息。最后，我们将研究记忆性CD 8 + T细胞在血管紧张素II反复刺激中的作用。这些研究将集中在CD 27和CD 70之间的相互作用的作用和来自CD 4+细胞的信号在CD 8+记忆细胞形成中的作用。总的来说，这些研究有望进一步加深我们对高血压的理解，并为这种常见且难以治疗的疾病提供新的治疗选择。

DESCRIPTION (provided by applicant): In the past several years, research from our laboratory and others has shown that innate and adaptive immunity play critical roles in the genesis of hypertension. The major hypothesis of this project is that the central nervous system coordinates actions of T cells, macrophages and dendritic cells, which in turn affect the vasculature and kidney to raise blood pressure. Studies in the past funding cycle indicate that actions of angiotensin II on circumventricular organs (CVOs) and in particular the subfornical organ (SFO) activate T cells and entry of these cells into the kidney and vasculature, where they promote vascular remodeling, vasoconstriction, salt and volume retention and ultimately blood pressure elevation. We have recently found that CD8+ T cells have a predominant role in the initial (first 2 week) response to angiotensin II and DOCA-salt challenge, and that mice lacking these cells display blunted hypertensive responses to angiotensin II and do not retain sodium and volume in response to angiotensin II. We propose that sympathetic stimuli, acting either on the kidney or secondary lymphoid organs activate dendritic cells (DCs), in part by stimulating DCs to produce reactive oxygen species (ROS) production. By deleting p22phox in the SFO using cre-lox technology, we will prevent the central actions of angiotensin II, and will conversely enhance the central actions of ang II by deleting SOD3 in the SFO. These interventions will determine if the actions of ang II on the SFO are critical for DC and renal CD8+ T cell activation. We will also examine if DC activation occurs predominantly in the spleen or in the kidney by performing selective renal denervation. Preliminary data indicate that angiotensin II increases DC superoxide production by 6 fold, largely via the Nox2 based NADPH oxidase. In aim 2, we will determine if central actions of angiotensin II promote DC ROS production and to perform studies to determine how this promotes CD8+ T cell activation. Bone marrow transplant of Nox2-/- cells will provide information regarding the role of DC Nox2 in hypertension. Finally, we will examine the role of memory CD8+ T cells in responses to repeated challenges with angiotensin II. These studies will focus on the roles of interactions between CD27 and CD70 and the roles of signals derived from CD4+ cells in CD8+ memory cell formation. Overall, these studies promise to further our understanding of hypertension and provide new therapeutic options for this common and difficult to treat disease.