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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：
10092213
负责人：
Maria Pilar Alcaide Alonso
金额：
$ 65.94万
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 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10092213
关键词：
Adhesions Adoptive Transfer Anti-Inflammatory Agents Antigen-Presenting Cells Antigens Biochemical Biological Assay CD4 Positive T Lymphocytes Cardiac Cause of Death Cell Adhesion Cells Clone Cells Coculture Techniques Complement Factor B Data Experimental Models Fibroblasts Fibrosis Goals Heart Heart failure Hospitalization Immune response Immunity Impairment In Vitro Inflammation Inflammation Mediators Inflammatory Knowledge Lead 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 RNA Reporting Role Signal Pathway Signal Transduction Site Source Sterility Syndrome T cell receptor repertoire sequencing T-Cell Activation T-Cell Receptor T-Lymphocyte T-cell receptor repertoire Testing Time Transforming Growth Factors Translating Tumor-infiltrating immune cells Work antifibrotic treatment base cell type clinical practice constriction coronary fibrosis draining lymph node experimental study heart function immune activation immunomodulatory strategy immunomodulatory therapies immunoregulation in vitro Assay in vivo inhibitor/antagonist 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.

这个新的R01应用的目的是研究T细胞活化的机制