Role of gammaHV68 M1 antigen in Vbeta4+ T cell expansion and fibrosis

描述（由申请人提供）：疱疹病毒疾病的发病机制与宿主免疫状态密切相关。鼠γ疱疹病毒68 (？HV68)为研究免疫正常与免疫缺陷宿主慢性伽玛疱疹病毒感染的结果提供了一个模型。？野生型小鼠的HV68感染在接种部位引起有限的急性感染，随后在多种组织和细胞类型中发生潜伏性、播散性感染。尽管野生型小鼠很少表现出任何与病毒相关的病理，干扰素受体缺陷宿主(IFN？R-/-)发展为潜在致命的全身性炎症性疾病。这种免疫介导的病理包括多器官纤维化组织损伤和血管炎，与潜伏病毒的慢性再激活和持续复制有关。有趣的是，这种疾病的许多特征在慢性感染a ？HV68突变体缺乏由M1开放阅读框（ORF）编码的抗原，尽管这种突变病毒在急性复制或建立潜伏感染方面没有受损。M1抗原与某些痘病毒蛇形蛋白（尽管它缺乏关键的催化残基）和？HV68分泌高亲和力趋化因子结合蛋白M3，已被证明可调节？HV68从延迟中重新激活。M1发挥这种作用的机制以及免疫系统参与的程度尚不清楚。在整个潜伏期过程中，？HV68抗病毒反应没有明显的刺激，但有一个明显的例外- V24+ CD8+ T细胞的显著扩增。我们最近的研究表明，这种反应需要M1抗原的表达。该应用程序旨在研究潜在的新机制，通过该机制？HV68 M1基因产物诱导V24+ T细胞活性，可能通过表达IFN-？这些T细胞可能在免疫功能低下的宿主中介导慢性疾病中发挥作用。本文提出以下3个目标：目标1：表征M1转录本结构和M1基因表达调控。目的2：明确m1诱导V24+ T细胞活化的机制及其对T细胞功能的影响。目的3：明确M1和V24+ T细胞在调节？HV68再激活、潜伏期和病毒诱导的全身性炎症疾病。

DESCRIPTION (provided by applicant): Herpesvirus disease pathogenesis is closely linked to host immune status. Murine gammaherpesvirus 68 (?HV68) provides a model for studying the outcome of chronic gammaherpesvirus infection in the immunocompetent versus immunodeficient host. ?HV68 infection of a wild-type mouse results in a limited, acute infection at the site of inoculation, followed by latent, disseminated infection in a variety of tissues and cell types. Although wild-type mice rarely display any virus-related pathology, interferon-gamma receptor- deficient hosts (IFN?R-/-) develop potentially lethal, systemic inflammatory disease. This immune-mediated pathology consists of multi-organ fibrotic tissue damage and vasculitis, associated with chronic reactivation of latent virus and persistent replication. Interestingly, many features of this disease are absent during chronic infection with a ?HV68 mutant lacking the antigen encoded by the M1 open reading frame (ORF) - even though this mutant virus is not impaired for either acute replication or establishment of a latent infection. The M1 antigen, which bears sequence homology to some pox virus serpins (although it lacks critical catalytic residues) and to the ?HV68 secreted high affinity chemokine binding protein M3, has been shown to regulate ?HV68 reactivation from latency. The mechanism by which M1 exerts this effect, and the extent of immune system involvement, is unknown. Throughout the course of latency, the ?HV68 antiviral response is not appreciably stimulated with one notable exception - the significant expansion of V24+ CD8+ T cells. We have recently shown that expression of the M1 antigen is required for this response. This application aims to study the potentially novel mechanism(s) by which the ?HV68 M1 gene product induces V24+ T cell activity, perhaps to self-limit reactivation from latency through expression of IFN-?, and the role such T cells might play in mediating chronic disease in an immunocompromised host. The following 3 aims are proposed: Aim 1: Characterize M1 transcript structure(s) and regulation of M1 gene expression. Aim 2: Define the mechanism of M1-induced V24+ T cell activation and its influence on T cell function. Aim 3: Define the role of M1 and V24+ T cells in regulating ?HV68 reactivation, latency, and virus-induced systemic inflammatory disease.