The non-classical CD8+ T cell response to murine cytomegalovirus

 描述（由申请方提供）：人巨细胞病毒（HCMV）是一种普遍存在的人类病原体，在健康个体中表现为无症状感染，并被免疫系统成功控制。HCMV能够在唾液腺的下颌下腺（SMG）内持续几个月，然后进入潜伏期，之后它可以周期性地和无症状地重新激活。然而，某些人群非常脆弱。对于新生儿和免疫功能低下的个体，由于其免疫健康下降，原发性和再活化感染都可能非常危险。CMV特异性CD 8 + T细胞的作用已被广泛研究。相反，非经典CD 8 + T细胞的功能尚未被检查。小鼠CMV是研究HCMV感染的成熟模型，这是由于其相似的发病机制、持久性以及经历潜伏和再活化的能力。使用该模型，我们的初步数据表明，非经典的CD 8 + T细胞响应MCMV而扩增，变得活化，并分泌炎性细胞因子。我的初步数据也排除了CD 1d作为限制性元件，但支持非经典MHC分子Qa-1的作用。基于这些数据，我建议确定非经典的CD 8 + T细胞在MCMV攻击过程中的作用，并确定其限制性元件和配体。在特定目标1中，我将确定MCMV感染期间非经典CD 8 + T细胞扩增所需的MHC Ib类限制性分子，以及公认的配体。在具体目标2中，我将确定MCMV扩增的非经典CD 8 + T细胞的具体作用。拟议的实验将有助于阐明非经典CD 8 + T细胞的免疫作用和对CMV感染的免疫反应，这是帮助限制免疫功能低下的个体和新生儿中出现的并发症的必要条件。

 DESCRIPTION (provided by applicant): Human cytomegalovirus (HCMV) is a ubiquitous human pathogen, which in healthy individuals presents as an asymptomatic infection and is successfully controlled by the immune system. HCMV is able to persist within the submandibular gland (SMG) of the salivary gland for a few months before entering a latency period, after which it can periodically and asymptomatically reactivate. However, certain populations are highly vulnerable. For neonates and immunocompromised individuals, both primary and reactivated infections can be extremely dangerous due to their decreased immune health. The role of CMV-specific CD8+ T cells has been extensively studied. Conversely, the function of non-classical CD8+ T cells has not been examined. Murine CMV is a well-established model to study HCMV infections, owing to its similar pathogenesis, persistence, and ability to undergo latency and reactivation. Using this model, our preliminary data demonstrate that non- classical CD8+ T cells expand in response to MCMV, become activated, and secrete inflammatory cytokines. My preliminary data also exclude CD1d as the restricting element, but support a role for the non-classical MHC molecule, Qa-1. Based on these data, I propose to determine the role of non- classical CD8+ T cells during MCMV challenge and to identify their restricting element and ligand. In Specific Aim 1, I will determine the MHC class Ib restriction molecule necessary for non-classical CD8+ T cell expansion during MCMV infection, as well as the recognized ligand. In Specific Aim 2, I will determine the specific role of MCMV expanded non-classical CD8+ T cells. The proposed experiments will help elucidate the immunological role of non-classical CD8+ T cells and the immune response to CMV infections, a necessity to help limit the complications seen in immunocompromised individuals and neonates.