Mechanisms of T cell activation in cardiac fibrosis and non-ischemic heart failure

心脏纤维化和非缺血性心力衰竭中 T 细胞激活的机制

基本信息

批准号：
10807275
负责人：
Maria Pilar Alcaide Alonso
金额：
$ 8.15万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10807275
关键词：
Adhesions Adoptive Transfer Anti-Inflammatory Agents Antigen Presentation Antigen-Presenting Cells Antigens Biochemical Biological Assay CD4 Positive T Lymphocytes Cardiac Cause of Death Cell Adhesion Cells Clone Cells Coculture Techniques Data Experimental Models Fibroblasts Fibrosis Goals Heart Heart failure Hospitalization Immune response Immunity Impairment In Vitro Inflammation Inflammation Mediators Inflammatory Knowledge Location Major Histocompatibility Complex Maps Mediastinal lymph node group Mediating Modeling Molecular Mus Myocardial Myocardial dysfunction Myofibroblast Pathogenesis Pathogenicity Pathway interactions Patients Pattern Pharmaceutical Preparations Phenotype Prevention approach Process Proliferating RNA Reporting Role Signal Pathway Signal Transduction Site Sorting Source Sterility Syndrome T cell infiltration T cell receptor repertoire sequencing T-Cell Activation T-Cell Receptor T-Lymphocyte T-cell receptor repertoire Testing Time Transforming Growth Factor beta Translating Work antifibrotic treatment aorta constriction cell type clinical practice coronary fibrosis draining lymph node experimental study heart function immune activation immunomodulatory strategy immunoregulation in vitro Assay in vivo inhibitor innovation knock-down mortality new therapeutic target novel prevent response spatiotemporal stem systemic inflammatory response time use

项目摘要

The goal of this new R01 application is to investigate the mechanisms of T cell activation and the consequences in the progression of cardiac fibrosis (CF) in the deadly syndrome of heart failure (HF), currently the leading cause of mortality and hospitalizations in the USA. We were the first to report cardiac T cell infiltration associated with CF in patients with non-ischemic HF, and using the well- established experimental model of HF induced by transverse aortic constriction (TAC), we and others described a major role for CD4+ T cells as major contributors to non-ischemic HF. However, due to the complexity of the mechanisms of T cell activation resulting in inflammation, CF and HF, no immunomodulatory or anti-fibrotic therapies have yet translated to clinical practice to treat HF. Our preliminary data reveal the novel finding that T cell activation occurs in the mediastinal lymph nodes that drain the heart (mLN), and also within the heart in a classic dependent manner that involves T cell receptor (TCR) engagement by antigens presented by Major histocompatibility complex II (MHC-II) expressed on antigen presenting cells (APC). We additionally demonstrate that activated cardiac fibroblasts (CFB) express MHC-II and thus could function as APC in the heart. Emerging evidence suggests that T cells can also be activated by alarmins, soluble inflammatory mediators produced in response to sterile inflammation, through TCR independent pathways in a “non classic" TCR- independent manner, and our in vitro and in vivo preliminary data is in support of this. Based on these findings, we will test the central hypothesis that classic and non-classic T cell activation mechanisms cooperate to initiate and sustain CF during the progression of HF. In aim 1, we will use Nur77GFP mice, in which T cells express GFP only when stimulated classically through the TCR, to map the specific location and timing of classic T cell activation during TAC. We will additionally perform single cell TCR sequencing on heart sorted GFP+CD4+ T cells to identify the immunodominant T cell clones in HF progression. The APC responsible for such activation and its effects in CF and HF over time will be evaluated in cell specific MHC-II-/- mice. In aim 2, we will perform adoptive transfer experiments of WT and alarmin sensing-impaired activated CD4+ T cells into MHC-II-/- recipient mice, which lack classic T cell activation and are normally protected from CF and HF. CF, cardiac function and the alarmins responsible for T cell activation will be characterized in in vivo and in vitro assays. In aim 3, based on our data indicating that activated T cell adhesion to CFB induces their transformation to pro-fibrotic myofibroblast in a TGFβ dependent manner, we will investigate the mechanisms of TGFβ synthesis, release and signaling in CFB in response to classically and non classically activated T cell adhesion. We will use in vitro biochemical and molecular assays. These important studies will result in a deeper understanding of how best to regulate T cell activation and T cell induced in HF and provide new perspectives on how to prevent, ameliorate and treat non-ischemic HF.

该新的R01应用的目的是研究T细胞激活的机制和心力衰竭致命综合征（HF）的心脏纤维化进展（CF）的后果，目前美国死亡率和住院的主要原因。我们是第一个报告心脏T细胞的人非缺血性HF患者与CF相关的浸润，并使用良好的实验性由横向主动脉收缩（TAC）诱导的HF模型，我们和其他人描述了CD4+ T的主要作用细胞作为非缺血性HF的主要因素。但是，由于T细胞机制的复杂性激活导致炎症，CF和HF，尚无免疫调节或抗纤维化疗法转化为治疗HF的临床实践。我们的初步数据揭示了T细胞激活的新发现发生在耗竭心脏（MLN）的纵隔淋巴结中，也发生在经典中涉及主要抗原T细胞受体（TCR）参与的依赖方式在抗原呈递细胞（APC）上表达的组织相容性复合物II（MHC-II）。我们另外证明激活的心脏成纤维细胞（CFB）表达MHC-II，因此可以在APC中起作用心。新兴的证据表明，T细胞也可以通过警报蛋白，可溶性炎症激活通过“非经典”中的TCR独立途径响应无菌炎症而产生的介体 TCR独立的方式以及我们的体外和体内初步数据支持这一点。基于这些调查结果，我们将测试经典和非经典T细胞激活机制合作的中心假设在HF进展过程中启动和维持CF。在AIM 1中，我们将使用NUR77GFP小鼠，其中T细胞仅在通常通过TCR刺激时表达GFP，以绘制特定位置和时间安排 TAC期间的经典T细胞激活。我们还将对心脏分类进行单细胞TCR测序 GFP+ CD4+ T细胞以鉴定HF进展中的免疫主导T细胞克隆。负责APC 随着时间的推移，将评估这种激活及其在CF和HF中的作用，将在细胞特异性MHC-II - / - 小鼠中进行评估。在AIM 2中，我们将对WT和Alarmin感应激活的CD4+ T细胞进行自适应转移实验 MHC-II - / - 受体小鼠，缺乏经典的T细胞激活，通常受到CF和HF的保护。 CF，心脏功能和负责T细胞激活的警报将在体内和体外表征测定。在AIM 3中，基于我们的数据，表明激活的T细胞粘合具有CFB的诱导以TGFβ的方式转化为纤维化的肌纤维细胞，我们将研究机制响应于经典和非经典激活的T细胞的TGFβ合成，在CFB中释放和信号传导粘附。我们将使用体外生化和分子测定法。这些重要的研究将导致更深入地了解如何最好地调节T细胞激活和HF中诱导的T细胞并提供新的T细胞关于如何预防，改善和治疗非缺血HF的观点。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Infarcted Myocardium Calls for T-Cell Help to Regulate Repair.

梗塞心肌需要 T 细胞帮助调节修复。

DOI：
10.1161/circresaha.123.322556
发表时间：
2023
期刊：
Circulation research
影响因子：
20.1
作者：
Li,Xudong;Alcaide,Pilar
通讯作者：
Alcaide,Pilar

Sialomucin CD43 Plays a Deleterious Role in the Development of Experimental Heart Failure Induced by Pressure Overload by Modulating Cardiac Inflammation and Fibrosis.

DOI：
10.3389/fphys.2021.780854
发表时间：
2021
期刊：
Frontiers in physiology
影响因子：
4
作者：
Kaur K;Velázquez FE;Anastasiou M;Ngwenyama N;Smolgovsky S;Aronovitz M;Alcaide P
通讯作者：
Alcaide P

Gut dysbiosis induced by cardiac pressure overload enhances adverse cardiac remodeling in a T cell-dependent manner.

DOI：
10.1080/19490976.2020.1823801
发表时间：
2020-11-09
期刊：
Gut microbes
影响因子：
12.2
作者：
Carrillo-Salinas FJ;Anastasiou M;Ngwenyama N;Kaur K;Tai A;Smolgovsky SA;Jetton D;Aronovitz M;Alcaide P
通讯作者：
Alcaide P

T-cell recruitment to the heart: friendly guests or unwelcome visitors?