T reg 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。肠道病毒（小核糖核酸病毒）和腺病毒最常涉及临床疾病。然而，这两种类型的病毒是非常常见的，并不是每个人都经历了肠道病毒/腺病毒感染会发展心肌炎。宿主和病毒因素共同决定病毒的致病性。我们已经开发了一种柯萨奇病毒B3心肌炎的小鼠模型，其中病毒的H3变体诱导严重的心肌炎，而H3病毒的突变体，命名为H310 A1，是非心肌炎。H3和H310 A1变体的不同之处在于VP 2衣壳蛋白中的单个非保守氨基酸突变。H310 A1变体刺激CD 4 + T调节（T reg）细胞，其主动抑制由H3病毒感染诱导的致病性免疫。T reg细胞为CD 4 + CD 25 + FoxP 3+。H3和H310 A1感染的主要区别在于H3病毒是系统性TNF α的有效诱导剂，而H310 A1感染几乎不诱导这种细胞因子。其他人和我们的研究表明，外源性给予重组TNF α会加重正常耐药小鼠的心肌炎易感性。因此，给予H310 A1感染的小鼠TNF α可恢复心肌炎易感性，并大大降低T reg细胞的TGF β表达。由于TGF β介导的免疫抑制至少由TH 3细胞，我们假设，TNF α调节TH 3细胞的活化或功能。这是令人惊讶的，因为据报道TNF α促进Tr 1型T reg细胞。TNFa可能对不同类型的T reg细胞的诱导具有不同的作用，促进一些而抑制其他。在目前的模型中，我们认为，TNF α可能废除T reg细胞通过诱导的CD 1d，一种非经典的MHC I类蛋白，和活化的T细胞表达的V？4 T细胞受体。小维4+细胞在病毒性心肌炎是CDID限制和过继转移的激活V？H310 A1感染的小鼠恢复心肌炎易感性。在本提案中，我们希望：1.确定T reg细胞是Tr 1、Th 3还是天然T reg细胞，这意味着它们应该通过IL-10、TGF β或细胞-细胞接触来抑制获得性免疫; 2.确定感染（TLR），TNF α，CD 1d和V？4+ T细胞产生或消除T reg细胞;和3.确定T reg细胞是抗原特异性（病毒）、心血管特异性（自身免疫）还是非抗原特异性。

DESCRIPTION (provided by applicant): Myocarditis is an inflammation of the myocardium which often follows microbial infections. Enteroviruses (picornaviruses) and adenoviruses are most frequently implicated in clinical disease. However, both types of virus are extremely common and not everyone experiencing an enterovirus/adenovirus infection will develop myocarditis. Both host and viral factors determine viral pathogenicity. We have developed a murine model of coxsackievirus B3 myocarditis where the H3 variant of the virus induces severe myocarditis while a mutant of the H3 virus, designated H310A1, is non-myocarditic. The H3 and H310A1 variants differ by a single non-conserved amino acid mutation in the VP2 capsid protein. The H310A1 variant stimulates CD4+ T regulatory (T reg) cells which actively suppress the pathogenic immunity induced by H3 virus infection. The T reg cells are CD4+CD25+FoxP3+. A major difference in H3 and H310A1 infections is that H3 virus is a potent inducer of systemic TNFa while H310A1 infection induces little of this cytokine. Studies by others and us have shown that exogenous administration of recombinant TNFa exacerbates myocarditis susceptibility in normally resistant mice. Thus, giving TNFa to H310A1 infected mice restores myocarditis susceptibility and greatly reduces TGF¿ expression by T reg cells. Since TGF¿ mediates immunosuppression at least by TH3 cells, we hypothesize that TNFa modulates TH3 cell activation or function. This is surprising since TNFa has been reported to promote the Tr1 type of T reg cell. It is possible that TNFa may have different effects on induction of distinct types of T reg cells, promoting some and inhibiting others. In the current model, we believe that TNFa might abrogate T reg cells through induction of CD1d, a non-classical MHC class I protein, and activation of T cells expressing the V?4 T cell receptor. V?4+ cells in viral myocarditis are CDId-restricted and adoptive transfer of activated V?4+ cells into H310A1 infected mice restores myocarditis susceptibility. In this proposal, we wish to: 1. Determine whether T reg cells are Tr1, Th3 or natural T reg cells which means they should suppress adaptive immunity through IL-10, TGF¿ or cell-cell contact; 2. Determine the relative roles of infection (TLR), TNFa, CD1d and V?4+ T cells in generation or abrogation of T reg cells; and 3. Determine whether the T reg cells are antigen specific (virus), cardiovascular specific (autoimmunity), or non-antigen specific.