T reg Cells in Myocarditis

描述（由申请人提供）：心肌炎是一种心肌炎症，通常由微生物感染引起。肠病毒（小核糖核酸病毒）和腺病毒最常与临床疾病有关。然而，这两种病毒都非常常见，并不是每个感染肠病毒/腺病毒的人都会患上心肌炎。宿主和病毒因素共同决定病毒的致病性。我们已经建立了柯萨奇病毒B3型心肌炎的小鼠模型，其中病毒的H3变体可诱导严重的心肌炎，而H3病毒的突变体H310A1则非心肌炎。H3和H310A1变体的不同之处在于VP2衣壳蛋白的一个非保守氨基酸突变。H310A1变异刺激CD4+ T调节性（T reg）细胞，积极抑制H3病毒感染诱导的致病性免疫。T细胞为CD4+CD25+FoxP3+。H3和H310A1感染的一个主要区别是，H3病毒是全身TNFa的有效诱导剂，而H310A1感染很少诱导这种细胞因子。我们和其他人的研究表明，外源性给药重组TNFa会加剧正常耐药小鼠的心肌炎易感性。由此可见，H310A1感染小鼠给予TNFa可恢复心肌炎易感性，并可显著降低T细胞TGF -¿的表达。由于TGF¿至少介导TH3细胞的免疫抑制，我们假设TNFa调节TH3细胞的激活或功能。这是令人惊讶的，因为有报道称TNFa可以促进T细胞的Tr1型。TNFa可能对不同类型T细胞的诱导有不同的作用，促进一些，抑制另一些。在目前的模型中，我们认为TNFa可能通过诱导CD1d（一种非经典MHC I类蛋白）和激活表达V？4 T细胞受体。V ?病毒性心肌炎的4+细胞受cdid限制，并过继转移活化的V？4+细胞注入H310A1感染小鼠可恢复心肌炎易感性。在这项建议中，我们希望：确定T细胞是Tr1、Th3还是天然T细胞，这意味着它们应该通过IL-10、TGF¿或细胞-细胞接触抑制适应性免疫；2. 确定感染（TLR）、TNFa、CD1d和V？4+ T细胞的产生或T细胞的消亡；和3。确定T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.