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

 描述(申请人提供)：人巨细胞病毒(HCMV)是一种普遍存在的人类病原体，在健康人中表现为无症状感染，并成功地由免疫系统控制。巨细胞病毒能够在唾液腺的颌下腺(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人来说，由于免疫健康水平下降，初次感染和再次感染都可能是极其危险的。CMV特异性CD8+T细胞的作用已被广泛研究。相反，非经典CD8+T细胞的功能尚未被检测。小鼠巨细胞病毒是研究巨细胞病毒感染的良好模型，由于其相似的发病机制、持久性以及经历潜伏期和再激活的能力。使用这个模型，我们的初步数据显示，非经典的CD8+T细胞对MCMV的反应是扩张的，被激活，并分泌炎性细胞因子。我的初步数据也排除了CD1d作为限制元件，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CD8+T细胞在MCMV攻击过程中的作用，并确定它们的限制因素和配体。在具体目标1中，我将确定MCMV感染过程中非经典CD8+T细胞扩增所必需的MHC Ib类限制分子，以及识别的配体。在特定目标2中，我将确定MCMV扩增的非经典CD8+T细胞的特定作用。拟议的实验将有助于阐明非经典CD8+T细胞的免疫学作用和对CMV感染的免疫反应，这是帮助限制免疫受损个人和新生儿出现的并发症的必要性。

 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.