T reg Cells in Myocarditis

心肌炎中的 T reg 细胞

基本信息

批准号：
7341114
负责人：
Sally A Huber
金额：
$ 38万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-01 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7341114
关键词：
Adenovirus Infections Adenoviruses Adoptive Transfer Amino Acids Animals Antigens Autoimmunity Blood CD4 Positive T Lymphocytes Capsid Proteins Cardiac Cardiac Myocytes Cardiovascular system Cells Class Clinical Coxsackie Viruses Dendritic Cells Disease Endothelial Cells Enterovirus Family Picornaviridae Generations Glycolipids Immune Immunity Immunosuppression Immunosuppressive Agents Infection Inflammation Interleukin-10 Lymphocyte Major Histocompatibility Complex Mediating Modeling Mus Mutation Myocarditis Myocardium Nature Numbers Pathogenicity Population Predisposition Recombinants Relative (related person)Reporting Resistance Role Spleen T-Cell Receptor T-Lymphocyte Therapeutic immunosuppression Transcriptional Activation Up-Regulation Variant Viral Virus Virus Diseases base cytokine experience in vivo killer T cell macrophage microbial mutant protein activation

项目摘要

DESCRIPTION (provided by applicant): Myocarditis is an inflammation of the myocardium which often follows microbial infections. Enteroviruses (picornaviruses) and adenoviruses are most frequently implicated in clinical disease. However, both types of virus are extremely common and not everyone experiencing an enterovirus/adenovirus infection will develop myocarditis. Both host and viral factors determine viral pathogenicity. We have developed a murine model of coxsackievirus B3 myocarditis where the H3 variant of the virus induces severe myocarditis while a mutant of the H3 virus, designated H310A1, is non-myocarditic. The H3 and H310A1 variants differ by a single non-conserved amino acid mutation in the VP2 capsid protein. The H310A1 variant stimulates CD4+ T regulatory (T reg) cells which actively suppress the pathogenic immunity induced by H3 virus infection. The T reg cells are CD4+CD25+FoxP3+. A major difference in H3 and H310A1 infections is that H3 virus is a potent inducer of systemic TNFa while H310A1 infection induces little of this cytokine. Studies by others and us have shown that exogenous administration of recombinant TNFa exacerbates myocarditis susceptibility in normally resistant mice. Thus, giving TNFa to H310A1 infected mice restores myocarditis susceptibility and greatly reduces TGF¿ expression by T reg cells. Since TGF¿ mediates immunosuppression at least by TH3 cells, we hypothesize that TNFa modulates TH3 cell activation or function. This is surprising since TNFa has been reported to promote the Tr1 type of T reg cell. It is possible that TNFa may have different effects on induction of distinct types of T reg cells, promoting some and inhibiting others. In the current model, we believe that TNFa might abrogate T reg cells through induction of CD1d, a non-classical MHC class I protein, and activation of T cells expressing the V?4 T cell receptor. V?4+ cells in viral myocarditis are CDId-restricted and adoptive transfer of activated V?4+ cells into H310A1 infected mice restores myocarditis susceptibility. In this proposal, we wish to: 1. Determine whether T reg cells are Tr1, Th3 or natural T reg cells which means they should suppress adaptive immunity through IL-10, TGF¿ or cell-cell contact; 2. Determine the relative roles of infection (TLR), TNFa, CD1d and V?4+ T cells in generation or abrogation of T reg cells; and 3. Determine whether the T reg cells are antigen specific (virus), cardiovascular specific (autoimmunity), or non-antigen specific.

描述（由申请人提供）：心肌炎是一种心肌炎症，通常由微生物感染引起，肠道病毒（小核糖核酸病毒）和腺病毒最常与临床疾病有关。然而，这两种类型的病毒都非常常见，并不是每个人都会感染肠道病毒。腺病毒感染会引起心肌炎。宿主和病毒因素共同决定了病毒的致病性。我们开发了柯萨奇病毒 B3 的小鼠模型。病毒的 H3 变种会引起严重的心肌炎，而 H3 病毒的突变体（称为 H310A1）则为非心肌炎。 H3 和 H310A1 变种的不同之处在于 VP2 衣壳蛋白中存在一个非保守氨基酸突变。变体刺激 CD4+ T 调节 (T reg) 细胞，主动抑制 H3 病毒感染诱导的病原免疫。 CD4+CD25+FoxP3+。H3 和 H310A1 感染的一个主要区别是 H3 病毒是全身性 TNFa 的有效诱导剂，而 H310A1 感染几乎不诱导这种细胞因子。其他人和我们的研究表明，外源性施用重组 TNFa 会加剧心肌炎的易感性。因此，给 H310A1 感染的小鼠注射 TNFa 可恢复心肌炎的易感性，并且大大降低TGF¿自 TGF 以来，T reg 细胞的表达。至少通过 TH3 细胞介导免疫抑制，我们认为 TNFa 调节 TH3 细胞的激活或功能，这是令人惊讶的，因为据报道 TNFa 可以促进 T reg 细胞的 Tr1 类型，TNFa 可能对不同的 T reg 细胞的诱导具有不同的作用。在当前模型中，我们认为 TNFa 可能通过诱导 CD1d（一种非经典 MHC 类别）来消除 T reg 细胞。 I蛋白和病毒性心肌炎中表达Vβ4T细胞受体的T细胞的激活是CDId限制的，并且将激活的Vβ4+细胞过继转移至H310A1感染的小鼠中可恢复心肌炎易感性。，我们希望： 1. 确定 T reg 细胞是 Tr1、Th3 还是天然 T reg 细胞，这意味着它们应该通过 IL-10、TGF 抑制适应性免疫。或细胞-细胞接触； 2. 确定感染 (TLR)、TNFa、CD1d 和 V?4+ T 细胞在 T reg 细胞生成或消除中的相对作用；以及 3. 确定 T reg 细胞是否具有抗原特异性（病毒）、心血管特异性（自身免疫）或非抗原特异性。