Innate Immunity 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。我们建立了柯萨奇病毒B3（CVB 3）心肌炎的小鼠模型。致病性需要病毒诱导强的抗原特异性CD 4 + Th 1（IFN+）细胞应答，而促进CD 4 + Th 2（IL-4+）应答的条件可预防心肌炎。表达V4 T细胞受体的T细胞对产生CD 4 + Th 1免疫至关重要。公认的是，先天效应物如+细胞调节适应性免疫应答。这种调节的公认机制取决于先天效应子释放的细胞因子，其提供有利于特异性Th应答的环境环境;以及先天效应子对抗原呈递细胞的影响，导致抗原呈递细胞的辅助分子或细胞因子表达的变化，从而导致CD 4+细胞应答的改变。据我们所知，我们是唯一的实验室假设+细胞直接结合到调节Th表型的CD 4+细胞。我们已经证明，+细胞选择性地杀死CD 4 + Th 2细胞，而留下完整的CD 4 + Th 1细胞。目前，几乎所有的研究都表明，CD 4 + Th 1细胞对Fas依赖的凋亡选择性易感，而CD 4 + Th 2细胞则明显抵抗。我们的数据与公认的知识截然相反。主要的问题是为什么在我们的CVB 3模型中，CD 4 + Th 2细胞是凋亡敏感的，以及在CVB 3感染的小鼠中，+细胞对Th 2细胞的选择性消除在多大程度上有助于CD 4 + Th 1优势。我们推测，在CD 4 + Th 1和Th 2细胞之间，CD 1d、Fas或抗凋亡因子（如c-FLIPL）存在差异，这些差异允许选择性杀伤Th 2细胞。在抗原刺激结束时消除效应CD 4+细胞可以节省造血区室中的资源和空间，但免疫收缩应适用于CD 4 + Th 1和Th 2细胞。仅CD 4 + Th 1细胞的收缩可允许CD 4 + Th 2的进行性积累和免疫系统的最终失衡。先天性效应细胞如+细胞在清除活化的CD 4 + Th 2细胞中可能起重要作用。这个提议的核心问题是先天效应器如何区分Th 1和Th 2细胞，杀死后者而不是前者。具体目标是：（2）确定CD 4+细胞上的CD 1d表达是否是体内CD 4+应答的+细胞免疫调节所必需的，以及V4+细胞产生IFN的作用;（3）检测CD 4 + Th 1和Th 2细胞克隆上CD 1d或Fas表达是否不同，并解释Th 2细胞克隆对V4+细胞诱导的凋亡的敏感性增加。和（4）确定CD 4 + Th 1和Th 2细胞之间的c-FLIPL表达是否不同，以及Th 1细胞中升高的水平是否保护它们免受V4+细胞介导的杀伤。.公共卫生相关性：该基金将研究Vgamma 4 + T细胞在通过Fas依赖机制选择性杀死活化的CD 4 + Th 2细胞中的作用，作为免疫应答后免疫收缩的方法。具体目的是：1）确定+细胞是否仅用于活化CD 4+细胞或维持体内活化的细胞。2)确定CD 4+细胞上的Fas或CD 1d表达是否是体内CD 4+应答的+细胞免疫调节所需，以及V4+细胞产生IFN的作用。3)确定CD 4 + Th 1或Th 2细胞克隆上的CD 1d或Fas表达是否不同，并解释Th 2克隆对V4+细胞诱导的凋亡的易感性增加。4)确定CD 4 + Th 1和Th 2细胞之间的c-FLIPL表达是否不同，以及Th 1细胞中的水平升高是否可保护它们免受V4+细胞介导的杀伤。

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. We have developed a murine model of coxsackievirus B3 (CVB3) myocarditis. Pathogenicity requires virus induction of a strong antigen-specific CD4+Th1 (IFN+) cell response while conditions which promote a CD4+Th2 (IL-4+) response prevent myocarditis. T cells expressing the V4 T cell receptor are crucial to generation of CD4+Th1 immunity. It is well accepted that innate effectors such as + cells modulate adaptive immune responses. The accepted mechanisms for this modulation depend upon cytokine release by the innate effectors which provides an environmental milieu favorable to a specific Th response; and innate effector impact on antigen presenting cells resulting in changes in accessory molecule or cytokine expression by the antigen presenting cells leading to alterations in CD4+ cell responses. To the best of our knowledge, we are the only laboratory hypothesizing that + cells directly bind to CD4+ cells modulating the Th phenotype. We have shown that + cells selectively kill CD4+Th2 cells leaving the CD4+Th1 cells intact. Currently, nearly all studies show that CD4+Th1 cells are selectively susceptible to Fas-dependent apoptosis while CD4+Th2 cells are remarkably resistant. Our data is diametrically opposite of accepted knowledge. The major question is why in our CVB3 model, CD4+Th2 cells are apoptosis susceptible and how much the selective elimination of Th2 cells by + cells contributes to the CD4+Th1 dominance in CVB3 infected mice. We hypothesize that there would be differences in CD1d, Fas or anti-apoptotic factors, such as c-FLIPL, between CD4+ Th1 and Th2 cells and that these differences allow the selective killing of the Th2 cells. Elimination of effector CD4+ cells at the end of antigenic stimulation conserves resources and space in the hemopoietic compartment, but immune contraction should apply to both CD4+Th1 and Th2 cells. Contraction of only CD4+Th1 cells could allow progressive accumulation of CD4+Th2 and ultimate imbalance of the immune system. Innate effectors such as + cells may play an important role in eliminating activated CD4+Th2 cells. The question central to this proposal is how innate effectors distinguish between Th1 and Th2 cells, killing the latter but not the former. The Specific Aims are: 1) Determine if + cells are only required for activating CD4+ cells or for maintaining the activated cells in vivo; (2) Determine if CD1d expression on CD4+ cells is required for + cell immunomodulation of the CD4+ response in vivo and the role of IFN production by V4+ cells; (3) Determine whether CD1d or Fas expression on CD4+ Th1 or Th2 cell clones differs and explains the increased susceptibility of Th2 clones to V4+ cell induced apoptosis.; and (4) Determine if c-FLIPL expression differs between CD4+Th1 and Th2 cells and elevated levels in Th1 cells protects them from V4+ cell mediated killing. . PUBLIC HEALTH RELEVANCE: This grant will investigate the role of Vgamma4+ T cells in selectively killing activated CD4+Th2 cells by Fas-dependent mechanisms, as a method for immune contraction after an immune response. The Specific Aims are to 1) Determine if + cells are only required for activating CD4+ cells or for maintaining the activated cells in vivo. 2) Determine if Fas or CD1d expression on CD4+ cells is required for + cell immunomodulation of the CD4+ response in vivo and the role of IFN production by V4+ cells. 3) Determine whether CD1d or Fas expression on CD4+ Th1 or Th2 cell clones differs and explains the increased susceptibility of Th2 clones to V4+ cell induced apoptosis. 4) Determine if c-FLIPL expression differs between CD4+Th1 and Th2 cells and whether elevated levels in Th1 cells protects them from V4+ cell mediated killing.