CD8+ T cell effectors against microsporidia

对抗微孢子虫的 CD8 T 细胞效应

基本信息

批准号：
8892976
负责人：
IMTIAZ AHMED KHAN
金额：
$ 39.92万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-17 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8892976
关键词：
AIDS/HIV problem Acquired Immunodeficiency Syndrome Adopted Albendazole Animals Biological Assay Blood Body Weight decreased CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cell Communication Cells Child Clinical Data Defect Development Diagnosis Diarrhea Effector Cell Elderly Encephalitozoon cuniculi Encephalitozoon hellem Enterocytozoon bieneusi Exhibits Generations Geographic Locations Goals HIV HIV Infections Hand Health Heterogeneity Human Immune Immune response Immunity Immunocompromised Host Immunotherapeutic agent Impairment Individual Infection Interferons Kinetics Knock-out Laboratories Lead Link Maintenance Mediating Memory Methods Microsporidia Microsporidiosis Modeling Mono-S Mus Opportunistic Infections Organ Transplantation Organism Parasite Control Parasites Patients Persons Pharmaceutical Preparations Play Population Population Study Predisposition Prevalence Production Risk Role Septata intestinalis Source Symptoms System Systemic disease T cell response T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Transplant Recipients Vaccines Viral adaptive immunity base cytokine fumagillin improved interest novel therapeutic intervention oral infection pathogen perforin response socioeconomics

项目摘要

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.

描述（由申请人提供）：微孢子虫感染仍然是 HIV 感染者面临的一个问题，并且是这些人持续性腹泻和全身性疾病的原因之一。最近的研究还表明，这些病原体会导致 HIV 阴性人群患病。对兔脑炎寄生虫（一种可以在实验室中轻松培养的微孢子虫）进行的有限研究已经证明了 T 细胞在预防寄生虫方面的重要性。亚群中，CD8+ T 淋巴细胞是负责保护性免疫的主要效应细胞，CD4+ 和 ?T 发挥着重要的辅助作用。敲除缺乏这两个亚群中的任何一个的动物，对兔 E. cuniculi 感染表现出次优的 CD8+ T 细胞免疫。我们实验室的研究表明，IL-21（一种由 CD4 和 γ T 细胞产生的细胞因子）对于诱导多功能 CD8+T 细胞针对病原体的中和反应非常重要。多功能或多功能 CD8+ T 细胞的重要性最近与增加有关。尽管尚未建立直接联系，但 IL-21 介导的多功能 CD8+ T 细胞反应是防止兔 E.cuniculi 感染的关键，该感染对 HIV 感染人群构成风险。具体的第一个具体目标是评估 ? 和 CD4+ T 细胞群响应兔 E. 感染的 IL-21 反应动力学。 IL-21 产生和启动 CD8+ T 细胞针对病原体的反应的机制。在第二个具体目标中，将确定IL-21在多功能CD8+T细胞效应反应中的作用，并且将分析多功能性在稳健的长期反应中的重要性。第三个也是最后一个具体目标将测试可在免疫受损（如感染 HIV 的）宿主中诱导和维持多功能 CD8+ T 细胞反应的各种策略，并将评估 IL-21 在这种情况下的治疗作用。对其他机会性感染和病毒病原体也有影响，其中强有力的 CD8+ T 细胞反应的发展对于宿主保护至关重要。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Intrinsic TGF-β signaling promotes age-dependent CD8+ T cell polyfunctionality attrition.

内在的 TGF-β 信号促进年龄依赖性 CD8 T 细胞多功能性消耗。

DOI：
10.1172/jci70522
发表时间：
2014-06-02
期刊：
The Journal of clinical investigation
影响因子：
0
作者：
R. Bhadra;M. Moretto;J. C. Castillo;C. Petrovas;S. Ferr;o;o;U. Shokal;M. Leal;R. Koup;I. Eleftherianos;I. Khan
通讯作者：
I. Khan

IL-21 Is Important for Induction of KLRG1+ Effector CD8 T Cells during Acute Intracellular Infection.

IL-21 对于急性细胞内感染期间 KLRG1 效应 CD8 T 细胞的诱导非常重要。