CD8+ T cell effectors against microsporidia

描述(由申请人提供)：微孢子虫感染仍然是艾滋病毒感染者的一个问题，并与这些人持续腹泻和系统性疾病的原因有关。最近的研究还表明，这些制剂会导致旅行者和免疫能力强的老年人等艾滋病毒阴性群体患病。楔形脑孢子虫是一种可以在实验室轻松培养的微孢子虫，现有的有限研究表明T细胞在预防这种寄生虫方面的重要性。在T细胞亚群中，CD8+T细胞是主要的保护性免疫效应细胞，其中CD4+T细胞起着重要的辅助作用。缺乏这两个亚群中任何一个的敲除动物表现出对楔形艾美耳球虫感染的次优CD8+T细胞免疫力。我们实验室最近的研究表明，IL-21是一种由CD4和βT细胞产生的细胞因子，在诱导多功能CD8+T细胞对病原体的反应中起重要作用。中和IL-21反应会导致多功能CD8+T细胞反应减少，单功能CD8+T细胞反应增加，导致它们的保护性降低，宿主不能有效地清除感染。最近，多功能或多功能CD8+T细胞的重要性与增强对病毒病原体的保护有关，尽管这种直接联系尚未建立。由此可见，IL-21介导的多功能CD8+T细胞应答是预防人类免疫缺陷病毒(HIV)感染的关键。该提案包括三个具体目标。在第一个特定目标中，我们将评估白介素21和CD4+T细胞群对楔形艾美耳球虫感染的反应动力学。IL-21的产生和CD8+T细胞对病原体应答的启动机制将被检测。在第二个特定目标中，将确定IL-21在多功能CD8+T细胞效应反应发展中的作用。此外，还将分析多功能性在发展强有力的长期反应中的重要性。在第三个也是最后一个特定目标中，将测试在免疫受损(如HIV感染)宿主中诱导和维持多功能CD8+T细胞反应的各种策略，并评估IL-21在这种情况下的治疗作用。这些研究将对其他机会性感染和病毒病原体产生深远影响，在这些病原体中，发展强大的CD8+T细胞反应对于宿主保护至关重要。 公共卫生相关性：微孢子虫感染给免疫功能低下的患者带来了问题，比如那些携带艾滋病毒感染的患者。这项建议的目标是了解控制这种病原体所需的免疫反应，以便免疫治疗剂需要保护免疫缺陷的受试者并被开发出来。

DESCRIPTION (provided by applicant): Microsporidial infection continues to be a problem for HIV infected individuals and are associated as a cause of persistent diarrhea and systemic disease in these people. Recent studies have also implicated these agents in causing illness to HIV- negative groups like travelers and immuno-competent elderly individuals. The limited studies available with Encephalitozoon cuniculi, a microsporidia that can be easily cultured in the laboratory have demonstrated importance of T cells in protection against the parasite. Amongst the T cell subsets, CD8+ T lymphocytes are primary effector cells responsible for protective immunity with CD4+ and ?¿ T playing an important helper role. Knock out animals lacking either of the two subsets exhibit sub-optimal CD8+ T cell immunity to E.cuniculi infection. Recent studies from our laboratory suggest that IL- 21, a cytokine produced by both CD4 and ?¿ T cells, is important for the induction of multifunctional CD8+T cell response against the pathogen. Neutralization of IL-21 response leads to decreased polyfunctional and increased mono-functional CD8+ T cell response as a result of which they are less protective and the host is unable to clear infection in an efficient manner. Importance of poly or multifunctional CD8+ T cells has recently been associated with increased protection against viral pathogens, although the direct link has yet to established. Thus it appears that IL-21 mediated polyfunctional CD8+ T cell response is key to protection against E.cuniculi infection which poses a risk to HIV infected population. The proposal comprises of three specific aims. In the first specific aim the kinetics o IL-21 response by ?¿ and CD4+ T cell population in response to E.cuniculi infection will be evaluated. The mechanism of IL-21 production and priming of CD8+ T cell response against the pathogen will be assayed. In the second specific aim role of IL-21 in the development of polyfunctional CD8+ T cell effector response will be determined. Further, importance of polyfunctionality in the development of robust long-term response will be analyzed. In the third and final specific aim various strategies which can lead to induction and maintenance of polyfunctional CD8+ T cell response in immunocompromised (like HIV-infected) host will be tested and therapeutic role of IL-21 in this situation will be evaluated. These studies will have fr reaching implications in other opportunistic infections and viral pathogens where development of robust CD8+ T cell response is critical for host protection. PUBLIC HEALTH RELEVANCE: Microsporidial infection poses a problem for immunocompromised patients like those carrying HIV infection. The goal of this proposal is to understand the immune response needed for the controlling this pathogen so that immunotherapeutic agents needed to protect immuno-deficient subjects and be developed