IL- 21 and Immune Mediated Viral Control

描述（由申请方提供）：深入了解调节抗病毒T细胞应答的诱导、质量和寿命的因素对于设计合理的策略来对抗病毒感染至关重要。强大的抗病毒免疫的标志是有效的CD 4和CD 8 T细胞应答的精心制作，其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的发展并决定记忆T细胞出现的信号尚未完全理解。该提案的目的是利用令人信服的初步发现，这些发现表明IL-21在抗病毒免疫中起着至关重要的作用。我们的初步研究清楚地表明，没有足够水平的IL-21，多功能效应CD 8 T细胞的产生受到损害，并且在慢性感染期间非常显著地加剧了T细胞耗竭。值得注意的是，在不存在IL-21的情况下表现出的抗病毒CD 8 T细胞中的许多表型和功能损伤类似于在CD 4 T细胞缺陷型宿主中观察到的缺陷。IL-21的主要产生者是CD 4滤泡辅助细胞（Tfh），其功能是帮助抗体应答，因此Tfh衍生的IL-21可能是帮助CD 8 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CD 8 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的基本细胞来源，以及基于IL-21的治疗是否在急性和慢性感染期间对病毒控制具有治疗益处。因此，我们提出以下具体目标：（1）。确定IL-21对多功能抗病毒CD 8 T细胞的直接作用。2）。阐明CD 4 T细胞来源的IL-21在促进抗病毒免疫中的作用。3）。定义在人类病毒感染期间产生IL-21的CD 4 T细胞的意义4）。确定IL-21对抗病毒免疫和控制的治疗效果。

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.