Tregulatory cells in myocarditis

描述（由申请人提供）：心肌炎是一种心肌炎症，通常发生在微生物感染之后，有证据表明对心脏抗原的自身免疫有助于心脏损伤。肠病毒，包括柯萨奇B3病毒（CVB3），是引起这种临床疾病的主要病原。CVB3诱导的心肌炎小鼠模型具有人类疾病的许多特征。免疫通常分为先天（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适应性免疫反应的质量和数量。两种先天效应是：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个TCR链之一的不变自然杀伤T细胞（iNKT）。在CVB3诱导的心肌炎中，34 T细胞的V34亚群对于诱导对心脏抗原和心脏炎症的自身免疫至关重要，而iNKT细胞具有保护作用。V34和iNKT细胞都对CD1d起反应，CD1d是一种非经典的主要组织相容性复合体1类分子。CD1d不仅在树突状细胞和巨噬细胞等抗原提呈细胞上表达，而且在CVB3感染小鼠的CD4 T细胞上也表达上调，包括CD4+CD25+FoxP3+ T调节细胞亚群。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作用。我们提供的证据表明，CVB3感染小鼠中的34个T细胞抑制T调节性细胞反应，而iNKT细胞促进T调节性细胞反应。我们假设34t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哪一种先天效应占主导地位。我们建议使用两个已建立的CVB3变异体H3和H310A1，它们已经被克隆和测序。H3病毒激活34个T细胞，未能激活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的差异，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。具体目标将确定：1)34 T细胞和iNKT细胞控制T调节性细胞激活的机制，以及这两种效应物如何相互抵消，影响适应性免疫的发展；2)为什么H3和H310A1激活T调节细胞的能力不同。

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.