Regulation of T cell immune response in Heart Failure with Preserved Ejection Fraction

此R01应用程序的目标是研究T细胞导致心力衰竭的机制 (HF)射血分数(HFpEF)保留，大约50%的HF患者受到影响。值得注意的是， 改善射血分数降低的心衰患者生存率和预后的治疗(HFrEF) 没有为HFpEF患者提供临床益处，他们经常出现多种并发症， 包括肥胖和高血压。HFpEF患者的相关流行病学研究表明， 炎症对HFpEF的贡献。然而，潜在的免疫机制在很大程度上仍然 未被开发的。在临床前模型中复制的人HFpEF的独特心肌标志 心脏代谢性HFpEF是未折叠蛋白反应(UPR)的下调，导致 细胞无法应对内质网(ER)应激，这是UPR的核心功能，因此 损害心肌细胞的松弛。我们使用心脏代谢实验模型的初步数据 HFpEF揭示了心脏T细胞浸润与舒张期功能障碍并存的新发现 心肌细胞肥大，T细胞缺陷小鼠(TCRA-/-)不会出现舒张期功能障碍或 在相同条件下心肌细胞肥大。我们的数据还显示，编码特定基因的 内质网应激反应因子，如X-box蛋白1(XBP1s)和激活转录因子6(ATF6)， 心脏代谢性HFpEF小鼠分离的CD4+T细胞显著下调，而T细胞不下调 来自带有HFrEF的小鼠。T细胞下调XBP1s与增强T细胞效应有关 功能和抗肿瘤活性。这一提议将检验T细胞调节失调的中心假设- 内质网应激反应促进心脏代谢性HFpEF的有害炎症。在Aim1，我们将 用单细胞抗体和RNA测序(CITE-SEQ)揭示T细胞转录图谱 在WT小鼠心脏代谢性HFpEF的整个发展过程中，研究 T细胞反应、所涉及的主要T细胞亚群及其拯救保护性表型的能力 在TCRA/-受体小鼠中观察到。在目标2中，我们将测定T细胞UPR在 心脏代谢性HFpEF的研究进展和利用增益性和失效性方法来确定 心脏代谢性HFpEF中T细胞UPR受损并影响T细胞前体的机制 炎症效应功能。在目标3中，我们将研究T细胞内在内质网应激的功能作用 HFpEF和T细胞分化过程中心肌细胞肥大和功能的反应 受损的UPR改变的影响心肌细胞肥大和功能的因素 在T细胞中选择性地缺乏UPR效应器，并获得功能途径。 上述目标的成功实现有望识别新的T细胞内在机制 这促进了HFpEF的有害免疫反应，为开发新的 免疫调节策略来对抗这种致命的综合症。

The goal of this R01 application is to investigate the mechanisms by which T cells contribute to heart failure (HF) with preserved ejection fraction (HFpEF), affecting roughly 50% of the HF patients. Notably, the treatments that improve survival and outcomes in patients with HF with reduced ejection fraction (HFrEF) have not provided clinical benefit in HFpEF patients, who often present with multiple comorbidities that include obesity and hypertension. Correlative epidemiological studies in HFpEF patients, suggest a potential contribution of inflammation to HFpEF. However the underlying immune mechanisms remain largely unexplored. A unique myocardial hallmark of human HFpEF replicated in a pre-clinical model of cardiometabolic HFpEF is the downregulation of the unfolded protein response (UPR), which results in the cellular inability to cope with endoplasmic reticulum (ER) stress, the central function of the UPR, thus impairing cardiomyocyte relaxation. Our preliminary data using an experimental model of cardiometabolic HFpEF reveal the novel finding that cardiac T cell infiltration co-exists with diastolic dysfunction and cardiomyocyte hypertrophy, and that T cell deficient mice (Tcra-/-) do not develop diastolic dysfunction or cardiomyocyte hypertrophy under the same conditions. Our data also reveal that genes encoding specific ER stress response factors such as X-box protein 1 (XBP1s) and activating transcription factor 6 (ATF6), are remarkably downregulated in CD4+ T cells isolated from mice with cardiometabolic HFpEF, and not in T cells from mice with HFrEF. T cell downregulation of XBP1s has been implicated in enhanced T cell effector function and anti-tumor activity. This proposal will test the central hypothesis that dysregulation of T cell- intrinsic ER stress responses promotes detrimental inflammation in cardiometabolic HFpEF. In Aim1, we will use single cell antibody and RNA sequencing (CITE-Seq) to uncover the T cell transcriptional profiles throughout the development of cardiometabolic HFpEF in WT mice, investigate the antigen dependence of the T cell response, the dominant T cell subsets involved, and their ability to rescue the protective phenotype observed in Tcra-/- recipient mice. In Aim 2, we will determine the expression of the T cell UPR during the progression of cardiometabolic HFpEF and utilize gain-and loss-of- function approaches to define the mechanisms by which the T cell UPR is compromised in cardiometabolic HFpEF and impacts T cell pro- inflammatory effector function. In Aim 3, we will investigate the functional role of the T cell-intrinsic ER stress response in cardiomyocyte hypertrophy and function during the progression of HFpEF and the T cell derived factors altered by the compromised UPR that impact cardiomyocyte hypertrophy and function, using mice selectively lacking UPR effectors in T cells, and gain of function approaches,. Successful accomplishment of the Aims proposed is expected to identify novel T cell intrinsic mechanisms that foster detrimental immune responses in HFpEF, paving the way for the development of new immunomodulatory strategies to confront this deadly syndrome.