Tregulatory cells in myocarditis

心肌炎中的调节细胞

• 批准号: 8119246
• 负责人: Sally A Huber
• 金额: $ 38.06万
• 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 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8119246
• 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. PUBLIC HEALTH RELEVANCE: Myocarditis is an inflammation of the heart muscle which usually follows microbial infections. Disease depends upon activation of pathogenic CD4 T cells and optimal activation of these effectors depends upon a population of 34 T cells which prevent the activation of immunosuppressive T regulatory cells. The studies in this proposal will determine how 34 T cells prevent T regulatory cell activation. The hypothesis is that 34 T cells either interact with dendritic cells through CD1d to change the dendritic cells from a pro-inflammatory to an suppressive phenotype, or the 34 T cells directly interact with CD1d on a highly suppressive subpopulation of T regulatory cells killing them.

描述(由申请人提供)：心肌炎是一种心肌炎症，通常伴随着微生物感染，有证据表明对心脏抗原的自身免疫有助于心脏损伤。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具有许多人类疾病的特征。免疫通常分为先天(结构性存在或快速诱导，没有病原体特异性或非常广泛的特异性)和获得性(对诱导病原体的高度特异性反应)类型。很明显，先天免疫反应可以决定随后的获得性免疫反应的质量和数量。两种先天效应是：表达γ-βT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个TCR链之一的不变自然杀伤T细胞(INKT)细胞。在CVB3诱导的心肌炎中，34个T细胞的V34亚群在诱导对心脏抗原的自身免疫和iNKT细胞保护的心脏炎症中起着至关重要的作用。V34和iNKT细胞都对CD1d有反应，CD1d是一种非经典的主要组织相容性复合体1类分子。CD1d不仅表达在包括树突状细胞和巨噬细胞在内的抗原提呈细胞上，而且在CVB3感染的小鼠的CD4T细胞上表达上调，包括一组CD4+CD25+FoxP3+T调节细胞。此外，CD1d+T调节细胞亚群比同一感染动物的CD1d-T调节细胞具有更强的免疫抑制作用。我们提供的证据表明，在CVB3感染的小鼠中，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34T和iNKT细胞相互抵消，CVB3感染小鼠发展自身免疫和心肌炎的最终能力取决于哪一种先天效应占优势。我们建议使用两个已建立的CVB3变异体H3和H310A1，它们已经被克隆和测序。H3病毒激活34个T细胞，但不能激活T调节细胞，从而诱导心脏自身免疫。相比之下，H310A1病毒与H3病毒只有一个氨基酸的不同，它不能激活34个T细胞，诱导T调节细胞，也不能诱导自身免疫。具体目标将决定：1)34T和iNKT细胞控制T调节细胞激活的机制(S)以及这两个效应器如何在影响发育中的适应性免疫中相互制衡；以及2)为什么H3和H310A1激活T调节细胞的能力不同。 公共卫生相关性：心肌炎是一种心肌炎症，通常伴随着微生物感染。疾病依赖于致病的CD4T细胞的激活，而这些效应器的最佳激活依赖于34T细胞的群体，这阻止了免疫抑制T调节细胞的激活。这项提案中的研究将确定34个T细胞如何阻止T调节细胞激活。假设34T细胞通过CD1d与树突状细胞相互作用，将树突状细胞从促炎表型转变为抑制性表型，或者34T细胞通过高度抑制性T调节细胞亚群直接与CD1d相互作用，杀死CD1d。