CDI and Gamma Delta+ in Viral Myocarditis

病毒性心肌炎中的 CDI 和 Gamma Delta

• 批准号: 6640065
• 负责人: Sally A Huber
• 金额: $ 15.15万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6640065
• 关键词: CD1 molecule; CD95 molecule; Coxsackievirus; MHC class I antigen; T cell receptor; antigen presenting cell; apoptosis; cell cell interaction; cytotoxic T lymphocyte; disease /disorder model; genetically modified animals; helper T lymphocyte; immunopathology; immunoregulation; inflammation; laboratory mouse; myocarditis; receptor expression; tissue /cell culture; transfection; virus infection mechanism

DESCRIPTION (provided by applicant): Coxsackievirus B3 (CVB3) infection causes myocarditis and dilated cardiomyopathy. The pathogenic mechanisms of the disease are complex. Myocarditis susceptibility correlates with activation of T cells expressing the Vgamma4 T cell receptor (TCR), CD4+ Thi (IFNgamma+) and CD8+alphabeta TCR+ autoimmune cytolytic T cells (CTL). Myocarditis resistance correlates to activation of Vgamma1+ and CD4+Th2 (IL4+) cells, and the absence of autoimmune CD8+alphabeta TCR+ effectors. Vgamma4+ cells kill both CVB3-infected myocytes and CD4+Th2 cells in vitro, and comprise up to 50% of the inflammatory T cells in the heart. CD8+alphabeta TCR+ autoimmune CTL kill uninfected but not virus-infected myocytes, and are the second most populous inflammatory cells in myocarditis. Since both Vgamma4+ and CD8+alphabeta TCR+ cells are cytolytic to cardiac myocytes in vitro, either or both populations might contribute to cardiac injury in vivo. Vgamma4+ cells recognize CD1, a major histocompatibility complex (MHC) class I-like molecule which normally presents hydrophobic lipid or peptide antigens. The autoimmune CD8+alphabeta TCR+ cells recognize antigen presented by classical MHC class I molecules. The overall goal of this application is to define the relative contributions of Vgamma4+ and CD8+alphabeta TCR+ cells to myocarditis in vivo, and determine whether Vgamma4+ cells facilitate CD8+alphabeta TCR+ cell activation by promoting CD4+ Th1 cell responses. The Specific Aims are to: 1) determine the relative importance of Vgamma4+ cell mediated killing of myocytes or modulation of CD4+ cell phenotype and activation of CD8+alphabeta TCR+ CTL in myocarditis; 2) determine CD1d expression in pathogenic versus non-pathogenic CVB3 infections and the role for lipid or peptide antigens in the CD1d-restricted Vgamma4+ T cell response; and 3) determine whether Vgamma4+ cells kill CD4+Th2 cells through CD1 -restricted responses.

描述（由申请人提供）：Coxsackievivirus B3（CVB3）感染会导致心肌炎和扩张性心肌病。该疾病的致病机制很复杂。心肌炎的易感性与表达VGAMMA4 T细胞受体（TCR），CD4+ THI（IFNGAMMA+）和CD8+ Alphabeta TCR+自身免疫性细胞溶解T细胞（CTL）的T细胞的激活相关。抗心肌炎与Vgamma1+和CD4+Th2（IL4+）细胞的激活以及缺乏自身免疫性CD8+Alphabeta TCR+效应子的激活相关。 VGAMMA4+细胞在体外杀死了CVB3感染的肌细胞和CD4+ TH2细胞，并占心脏中高达50％的炎性T细胞。 CD8+ Alphabeta TCR+自身免疫性CTL杀死未感染的但未感染病毒的心肌细胞，并且是心肌炎中第二大大量炎症细胞。由于VGAMMA4+和CD8+ Alphabeta TCR+细胞在体外都是溶质状到心肌细胞的细胞溶液，因此或两个群体可能在体内导致心脏损伤。 VGAMMA4+细胞识别CD1是一种主要的组织相容性复合物（MHC）I类分子，通常呈现疏水性脂质或肽抗原。自身免疫性CD8+字母TCR+细胞识别经典MHC I类分子呈现的抗原。该应用的总体目标是定义VGAMMA4+和CD8+ Alphabeta TCR+细胞对体内心肌炎的相对贡献，并确定VGAMMA4+细胞是否通过促进CD4+ Th1细胞反应来促进CD8+ Alphabeta TCR+细胞激活。具体目的是：1）确定vgamma4+细胞介导的肌细胞杀死或CD4+细胞表型的调节的相对重要性，以及在心肌炎中CD8+ Alphabeta TCR+ CTL的激活； 2）确定致病性CVB3感染与非致病性CVB3感染中的CD1D表达，以及脂质或肽抗原在CD1D限制的VGAMMA4+ T细胞反应中的作用； 3）确定VGAMMA4+细胞是否通过CD1限制反应杀死CD4+ TH2细胞。