Tregulatory cells in myocarditis

心肌炎中的调节细胞

• 批准号: 8645714
• 负责人: Sally A Huber
• 金额: $ 37.36万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8645714
• 关键词: A Mouse; Affinity; Amino Acids; Animals; Antigen-Presenting Cells; Antigens; Autoimmunity; Avidity; Binding; CD4 Positive T Lymphocytes; CD55 Antigens; CVBR45; Calcium Signaling; Capsid Proteins; Cardiac; Cell physiology; Cells; Characteristics; Clinical; Coxsackie Viruses; Dendritic Cells; Development; Disease; Disease model; Enterovirus; Equilibrium; Fibrinogen; Generations; Heart; Histocompatibility Antigens Class I; IL2RA gene; Immune response; Immunity; Immunosuppressive Agents; Infection; Inflammation; Inflammatory; Injury; Interferon Type II; Investigation; Lymphoid Cell; MHC antigen; Mediating; Modeling; Mus; Myocarditis; Myocardium; Pathogenesis; Phenotype; Population; Publishing; Regulation; Regulatory T-Lymphocyte; Reporting; Signal Transduction; Specificity; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Variant; Virus; adaptive immunity; cell killing; gamma-delta T-Cell Receptor; human disease; killer T cell; killings; macrophage; microbial; mouse model; pathogen; prevent; response

DESCRIPTION (provided by applicant): Myocarditis is an inflammation of the heart muscle which often follows microbial infections and evidence indicates that autoimmunity to heart antigens contributes to cardiac injury. Enteroviruses, including coxsackievirus B3 (CVB3), are major etiological agents causing this clinical disease. A mouse model of CVB3 induced myocarditis shares many characteristics of the human disease. Immunity is usually divided into innate (constitutively present or rapidly induced and having either no pathogen specificity or very broad specificity) and adaptive (highly specific responses to inducing pathogen) types. It is clear that the innate immune response can determine both the quality and quantity of the subsequent adaptive immune response. Two innate effectors are: T cells expressing the gamma-delta T cell receptor (34 T cells) and invariant natural killer T (iNKT) cells which express an invariant T cell receptor 1 chain and one of a limited number of 2 TCR chains. In CVB3 induced myocarditis, the V34 subpopulation of 34 T cells is crucial to induction of autoimmunity to cardiac antigens and inflammation in the heart which iNKT cells are protective. Both V34 and iNKT cells react to CD1d, a non-classical major histocompatibility complex class 1-like molecule. CD1d is not only expressed on antigen presenting cells including dendritic cells and macrophage, but is also up-regulated on CD4 T cells in CVB3 infected mice, including a subpopulation of CD4+CD25+FoxP3+ T regulatory cells. Furthermore, the CD1d+ T regulatory cell subpopulation is substantially more immunosuppressive than the CD1d- T regulatory cells from the same infected animal. We provide evidence that 34 T cells in CVB3 infected mice inhibits T regulatory cell responses while iNKT cells promote T regulatory cell response. We hypothesize that 34 T and iNKT cells counter-balance each other and the ultimate ability of CVB3 infected mice to ddevelop autoimmunity and myocarditis depends upon which innate effector dominates. We propose to use two established CVB3 vartiants, H3 and H310A1, which have been cloned and sequenced. H3 virus activates 34 T cells, fails to activate T regulatory cells and induces cardiac autoimmunity. In contrast, H310A1 virus, which differs by a single amino acid from H3 virus, fails to activate 34 T cells, induces T regulatory cells and fails to induce autopimmunity. The Specific Aims will determine: 1) the mechanism(s) by which 34 T and iNKT cells control T regulatory cell activation and how these two effectors counter-balance each other in impacting developing adaptive immunity; and 2) why H3 and H310A1 differ in ability to activate T regulatory cells.

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，有证据表明对心脏抗原的自身免疫会导致心脏损伤。肠道病毒，包括柯萨奇病毒 B3 (CVB3)，是引起这种临床疾病的主要病原体。 CVB3 诱导的心肌炎小鼠模型与人类疾病有许多共同特征。免疫通常分为先天性（组成性存在或快速诱导，没有病原体特异性或非常广泛的特异性）和适应性（对诱导病原体的高度特异性反应）类型。显然，先天免疫反应可以决定随后的适应性免疫反应的质量和数量。两种先天效应细胞是：表达 γ-δ T 细胞受体的 T 细胞（34 个 T 细胞）和表达不变 T 细胞受体 1 链和有限数量的 2 条 TCR 链之一的不变自然杀伤 T (iNKT) 细胞。在 CVB3 诱导的心肌炎中，34 个 T 细胞的 V34 亚群对于诱导针对心脏抗原的自身免疫和心脏炎症至关重要，而 iNKT 细胞对此具有保护作用。 V34 和 iNKT 细胞均与 CD1d 发生反应，CD1d 是一种非经典主要组织相容性复合物 1 类分子。 CD1d 不仅在抗原呈递细胞（包括树突状细胞和巨噬细胞）上表达，而且在 CVB3 感染小鼠的 CD4 T 细胞（包括 CD4+CD25+FoxP3+ T 调节细胞亚群）上表达上调。此外，CD1d+ T 调节细胞亚群比来自同一感染动物的 CD1d- T 调节细胞具有更强的免疫抑制性。我们提供的证据表明，CVB3 感染小鼠中的 34 个 T 细胞抑制 T 调节细胞反应，而 iNKT 细胞促进 T 调节细胞反应。我们假设 34 T 和 iNKT 细胞相互平衡，CVB3 感染小鼠发展自身免疫和心肌炎的最终能力取决于先天效应细胞占主导地位。我们建议使用两个已建立的 CVB3 变异体 H3 和 H310A1，它们已被克隆和测序。 H3病毒可激活34个T细胞，但无法激活T调节细胞并诱导心脏自身免疫。相比之下，H310A1病毒与H3病毒只有一个氨基酸不同，无法激活34个T细胞，诱导T调节细胞，也无法诱导自身免疫。具体目标将确定： 1) 34 T 和 iNKT 细胞控制 T 调节细胞激活的机制，以及这两种效应器如何在影响适应性免疫发展中相互平衡； 2) 为什么 H3 和 H310A1 激活 T 调节细胞的能力不同。