Tregulatory cells in myocarditis

描述（由申请方提供）：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导致心脏损伤。肠道病毒，包括柯萨奇病毒B3（CVB 3），是导致这种临床疾病的主要病原体。CVB 3诱导的心肌炎的小鼠模型具有许多人类疾病的特征。免疫通常分为先天性（组成性存在或快速诱导，并且没有病原体特异性或具有非常广泛的特异性）和适应性（对诱导病原体的高度特异性反应）类型。很明显，先天免疫应答可以决定随后的适应性免疫应答的质量和数量。两种先天效应子是：表达γ-δ T细胞受体的T细胞（34 T细胞）和表达恒定T细胞受体1链和有限数量的2条TCR链之一的恒定自然杀伤T（iNKT）细胞。在CVB 3诱导的心肌炎中，34 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中的炎症是至关重要的，iNKT细胞是保护性的。V34和iNKT细胞均与CD 1d（一种非经典的主要组织相容性复合体1类分子）反应。CD 1d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CVB 3感染的小鼠中在CD 4 T细胞（包括CD 4 + CD 25 + FoxP 3 + T调节细胞亚群）上也上调。此外，CD 1d + T调节细胞亚群比来自同一感染动物的CD 1d-T调节细胞具有显著更强的免疫抑制性。我们提供的证据表明，在CVB 3感染小鼠的34 T细胞抑制T调节细胞的反应，而iNKT细胞促进T调节细胞的反应。我们假设34 T细胞和iNKT细胞相互平衡，CVB 3感染小鼠产生自身免疫和心肌炎的最终能力取决于哪种先天效应细胞占主导地位。我们建议使用两个已建立的CVB 3变异体，H3和H310 A1，这两个变异体已被克隆和测序。H3病毒激活34个T细胞，不能激活调节性T细胞并诱导心脏自身免疫。与此相反，H310 A1病毒与H3病毒只有一个氨基酸不同，它不能激活34 T细胞，诱导调节性T细胞，也不能诱导自身免疫。具体目标将确定：1）34 T和iNKT细胞控制调节性T细胞活化的机制，以及这两种效应物如何在影响发育中的适应性免疫中相互平衡;以及2）H3和H310 A1活化调节性T细胞的能力为何不同。

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.