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

描述（由申请方提供）：疱疹病毒病的发病机制与宿主免疫状态密切相关。鼠γ疱疹病毒68（？HV 68）提供了用于研究免疫活性宿主与免疫缺陷宿主中慢性γ疱疹病毒感染的结果的模型。?野生型小鼠的HV 68感染导致接种部位的有限的急性感染，随后在多种组织和细胞类型中潜伏的播散性感染。虽然野生型小鼠很少显示任何病毒相关的病理，干扰素γ受体缺陷型宿主（IFN？R-/-）发展成潜在致命的全身性炎性疾病。这种免疫介导的病理学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活化和持续复制有关。有趣的是，这种疾病的许多特点是缺乏在慢性感染？缺乏M1开放阅读框（ORF）编码的抗原的HV 68突变体-尽管该突变病毒的急性复制或潜伏感染的建立均未受损。M1抗原，它承担序列同源性的一些痘病毒丝氨酸蛋白酶抑制剂（虽然它缺乏关键的催化残基）和？HV 68分泌的高亲和力趋化因子结合蛋白M3，已被证明是调节？HV 68从潜伏期重新激活。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，？HV 68抗病毒应答没有被明显刺激，有一个显著的例外-V24+ CD 8 + T细胞的显著扩增。我们最近表明，M1抗原的表达是这种反应所必需的。本申请旨在研究潜在的新机制（S）？HV 68 M1基因产物诱导V24+ T细胞活性，可能通过表达IFN-γ自限潜伏期再激活，以及这种T细胞在免疫功能低下的宿主中介导慢性疾病中可能发挥的作用。目的1：研究M1转录本的结构和M1基因的表达调控。目的2：阐明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：确定M1和V24+ T细胞在调节？HV 68再激活、潜伏和病毒诱导的全身性炎症性疾病。

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.