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来对抗病毒感染至关重要。强大的抗病毒免疫的一个标志是有效的CD4和CD8 T细胞反应的阐述，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反应的发展和指示记忆T细胞出现的信号尚未完全了解。本提案的目的是利用令人信服的初步发现，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，如果没有足够水平的IL-21，多功能效应CD8 T细胞的产生就会受到损害，并且在慢性感染期间，T细胞衰竭会明显加剧。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的主要生产者是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，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CDS T细胞的直接作用。2）. 阐明CD4 T细胞来源的IL-21在促进抗病毒免疫中的作用。3）. 确定在人类病毒感染过程中产生il -21的CD4 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.