IL- 21 and Immune Mediated Viral 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，对于设计合理的策略对抗病毒感染至关重要。强大的抗病毒免疫的一个特点是阐述了强大的CD4和CD8T细胞反应，它们协同行动，带来感染的控制。无效应答的后果可能是灾难性的，导致病毒持续存在或失去长期的免疫记忆。然而，驱动最强大的多功能效应器反应的发展和指示记忆T细胞出现的信号还没有完全被理解。这项建议的目的是利用令人信服的初步发现，这些发现表明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，多功能效应器CD8 T细胞的生成会受到影响，相当引人注目的是，在慢性感染期间，T细胞的耗竭会加剧。值得注意的是，在缺乏IL-21的情况下，抗病毒CDS T细胞的许多表型和功能损害与在CD4T细胞缺陷宿主中观察到的缺陷相似。CD4滤泡辅助细胞(TFH)是产生IL-21的主要细胞，其功能是帮助抗体应答，因此TFH产生的IL-21可能是帮助CD8 T细胞应答的关键因子。然而，目前尚不清楚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的主要细胞来源，以及在急性和慢性感染期间，基于IL-21的治疗是否对病毒控制有疗效。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细胞的直接作用。2)。阐明CD4T细胞来源的IL-21在促进抗病毒免疫中的作用。3)。明确产生IL-21的CD4T细胞在人类病毒感染过程中的意义。测定IL-21抗病毒免疫和对照的疗效。

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.