Tregulatory cells in myocarditis

心肌炎中的调节细胞

基本信息

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
项目类别：
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

项目摘要

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）：心肌炎是心肌的炎症，通常遵循微生物感染，证据表明心脏抗原自身免疫性会导致心脏损伤。肠病毒，包括Coxsackievivirus B3（CVB3）是引起这种临床疾病的主要病因。 CVB3的小鼠模型诱导的心肌炎具有人类疾病的许多特征。免疫通常分为先天性（组成症存在或迅速诱导，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）。显然，先天免疫反应可以确定随后的适应性免疫反应的质量和数量。两个先天效应子是：表达伽马 - 戴尔塔T细胞受体（34个T细胞）和不变的天然杀伤t（inkt）细胞的T细胞，这些杀伤（inkt）表达不变的T细胞受体1链和有限数量的2个TCR链之一。在CVB3诱导的心肌炎中，34个T细胞的V34亚群对于诱导自身免疫性对心脏抗原和心脏的炎症至关重要。 V34和Inkt细胞都会对CD1D反应，CD1D是一种非经典的主要组织相容性复合物1类样分子。 CD1D不仅在包括树突状细胞和巨噬细胞在内的抗原呈递细胞上表达，而且在CVB3感染的小鼠的CD4 T细胞上也被上调，包括CD4+CD25+CD25+FOXP3+T调节细胞的亚群。此外，CD1D+ T调节细胞亚群比来自同一受感染动物的CD1D-T调节细胞的免疫抑制更大。我们提供的证据表明，CVB3感染小鼠的34个T细胞抑制了T调节细胞反应，而INKT细胞促进了调节细胞反应。我们假设34 T和Inkt细胞相互平衡，并且CVB3感染小鼠ddevelop自身免疫性和心肌炎的最终能力取决于哪些先天效应的主导者。我们建议使用已被克隆和测序的两个已建立的CVB3 VARTIANTS H3和H310A1。 H3病毒激活34个T细胞，无法激活T调节细胞并诱导心脏自身免疫性。相反，H310A1病毒与H3病毒的单个氨基酸不同，无法激活34个T细胞，诱导T调节细胞，并且无法诱导自动免疫。具体目的将确定：1）34 t和iNKT细胞控制调节细胞激活的机制，以及这两个效应子如何相互平衡在影响发展适应性免疫时相互平衡； 2）为什么H3和H310A1在激活T调节细胞的能力上有所不同。