IL- 21 and Immune Mediated Viral Control

IL-21 和免疫介导的病毒控制

• 批准号: 8067761
• 负责人: Allan J Zajac
• 金额: $ 46.59万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8067761
• 关键词: Acute; Antibody Formation; B-Lymphocytes; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Chronic; Defect; Dependency; Development; Generations; Helper-Inducer T-Lymphocyte; Heterogeneity; Human; Immune; Immunity; Immunologic Memory; Infection; Infection Control; Life; Longevity; Mediating; Play; Role; Shapes; Signal Transduction; Source; T cell response; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Therapeutic; Therapeutic Effect; Viral; Virus Diseases; base; combat; exhaustion; functional disability; response

DESCRIPTION (provided by applicant): Developing an in-depth understanding of the factors that regulate the induction, quality, and longevity of anti- viral T cell responses is essential for devising rational strategies to combat viral infections. A hallmark of robust anti-viral immunity is the elaboration of potent CD4 and CD8 T cell responses which act cooperatively to bring about control of the infection. The consequences of ineffective responses can be catastrophic, resulting in viral persistence or the loss of long-lived immunological memory. Nevertheless, the signals which drive the development of the most robust polyfunctional effector responses and dictate the emergence of memory T cells are not fully understood. The purpose of this proposal is to capitalize on compelling preliminary findings which indicate that IL-21 plays a vital role in anti-viral immunity. Our initial studies clearly show that without sufficient levels of IL-21 the generation of polyfunctional effector CD8 T cells is compromised, and quite strikingly T cell exhaustion is exacerbated during chronic infections. Significantly, many of the phenotypic and functional impairments in anti-viral CDS T cells which manifest in the absence of IL-21 resemble the defects observed in CD4 T cell deficient hosts. A principal producer of IL-21 are CD4 follicular helper cells (Tfh) which function to help antibody responses, therefore Tfh derived IL-21 may be the critical factor that helps CD8 T cell responses. It is, however, unclear whether IL-21 is acting directly or indirectly on anti-viral CD8 T cells to promote their functionality, how T cell heterogeneity is shaped by IL-21, whether Tfh are the essential cellular sources of IL-21, and whether IL-21 based treatments have therapeutic benefits on viral control both during acute and chronic infection. We therefore propose the following specific aims: 1). Determine the direct effects of IL-21 on polyfunctional anti-viral CDS T cells. 2). Elucidate the role of CD4 T cell-derived IL-21 in promoting anti-viral immunity. 3). Define the significance of IL-21-producing CD4 T cells during viral infections of humans 4). Determine the therapeutic effects of IL-21 on anti-viral immunity and control.

描述（由申请人提供）：深入了解调节抗病毒 T 细胞反应的诱导、质量和寿命的因素对于制定对抗病毒感染的合理策略至关重要。强大的抗病毒免疫的一个标志是产生有效的 CD4 和 CD8 T 细胞反应，它们协同作用以控制感染。无效反应的后果可能是灾难性的，导致病毒持续存在或长期免疫记忆的丧失。然而，驱动最强大的多功能效应器反应发展并决定记忆T细胞出现的信号尚不完全清楚。该提案的目的是利用令人信服的初步结果，这些结果表明 IL-21 在抗病毒免疫中发挥着至关重要的作用。我们的初步研究清楚地表明，如果没有足够水平的 IL-21，多功能效应 CD8 T 细胞的生成就会受到损害，并且令人惊讶的是，在慢性感染期间 T 细胞耗竭会加剧。值得注意的是，在缺乏 IL-21 的情况下，抗病毒 CDS T 细胞中表现出的许多表型和功能损伤类似于在 CD4 T 细胞缺陷宿主中观察到的缺陷。 IL-21 的主要产生者是 CD4 滤泡辅助细胞 (Tfh)，其功能是帮助抗体反应，因此 Tfh 衍生的 IL-21 可能是帮助 CD8 T 细胞反应的关键因素。然而，尚不清楚 IL-21 是否直接或间接作用于抗病毒 CD8 T 细胞以促进其功能、IL-21 如何塑造 T 细胞异质性、Tfh 是否是 IL-21 的重要细胞来源、基于 IL-21 的治疗是否对急性和慢性感染期间的病毒控制具有治疗效果。因此，我们提出以下具体目标：1）。确定 IL-21 对多功能抗病毒 CDS T 细胞的直接影响。 2）。阐明 CD4 T 细胞衍生的 IL-21 在促进抗病毒免疫中的作用。 3）。定义人类病毒感染过程中产生 IL-21 的 CD4 T 细胞的重要性 4)。确定 IL-21 对抗病毒免疫和控制的治疗效果。