Immunobiology of Regulatory T Cells in HIV Infection

描述（由申请人提供）：免疫系统已经进化出多种调节机制来保护宿主免受病原体的侵害，而不会通过未经检查的反应自我施加免疫病理。现在有令人信服的证据表明，CD4+CD25+ (Tregs) T细胞亚群在自身和微生物抗原刺激下抑制T细胞激活。我们之前假设Tregs在HIV感染期间调节T细胞激活中起关键作用。为了支持这一假设，最近，我们的实验室和其他人的结果表明，treg在疾病的晚期阶段被破坏，并在感染的早期阶段损害hiv特异性免疫。这些发现表明Tregs在HIV感染过程中可能是一把双刃剑，了解它们如何微调免疫激活可能会揭示HIV发病机制的重要线索。在人类Treg细胞发育和功能的免疫生物学方面仍有许多关键的空白。目前还不清楚treg是否特异性识别HIV抗原，以及在HIV感染过程中是否具有有益或有害的作用。基于我们的新发现和将幼稚T细胞重编程为Treg的创新方法，我们准备着手解决有关Treg发育机制，功能和对HIV感染易感性的一些关键问题。为了实现这些目标，我们建议确定：1)人类Treg发育和扩增的激活参数；2)Treg对TCR刺激反应性低的分子基础；并利用前两个目标的工具和知识，3)确定Tregs的抗原特异性以及它们是否抑制hiv特异性免疫反应。拟议的研究将产生一个重要的细胞和分子框架，以了解Tregs和HIV之间的体内相互作用。我们还预计，从这项研究中获得的结果将有助于合理设计新的策略，以治疗性地操纵免疫系统的调节臂。事实上，treg的下调可能被证明在增强疫苗对艾滋病毒和其他人类病原体的功效方面是非常有益的。

DESCRIPTION (provided by applicant): The immune system has evolved multiple regulatory mechanisms to protect the host from pathogens without the self-infliction of immune pathology through an unchecked response. There is now compelling evidence that a subset of T cells defined as CD4+CD25+ (Tregs), suppress T cell activation in response to both self and microbial antigen stimulation. We previously hypothesized that Tregs play a critical role in modulating T cell activation during HIV infection. In support of this hypothesis, recently, results from our lab and others showed that Tregs are disrupted during late stages of the disease and impair HIV-specific immunity during earlier stages of the infection. These findings suggest Tregs may act as a double-edged sword during HIV infection and understanding how they fine tune immune activation will likely reveal important clues to HIV pathogenesis. Many critical gaps remain in the immunobiology of human Treg cell development and function. It is also unclear whether Tregs specifically recognize HIV antigens and have a beneficial or harmful role during HIV infection. Based on our novel findings and innovative methods to reprogram naive T cells into Tregs, we are poised to embark on addressing a number of key questions concerning the mechanism of Treg development, function and susceptibility to HIV infection. To achieve these goals we propose to determine: 1) the activation parameters of human Treg development and expansion, 2) the molecular basis of Treg hyporesponsiveness to TCR stimulation; and using the tools and knowledge from the first two aims, 3) to define antigen specificity of Tregs and whether they suppress HIV-specific immune response. The proposed studies will yield an important cellular and molecular framework to understand the in vivo interplay between Tregs and HIV. It is also anticipated that results gained from this study will facilitate the rational design of new strategies to therapeutically manipulate the regulatory arm of the immune system. Indeed, downregulation of Tregs may prove to be highly beneficial in terms of bolstering the efficacy of vaccines to HIV and other human pathogens.