Regulation of CD8+ T cell immunity to tuberculosis

项目摘要。结核分枝杆菌（Mtb）造成的人类死亡人数比任何 其他病原体。结核分枝杆菌在人体中引起强烈的CD 8 T细胞反应，而CD 8 T细胞是结核分枝杆菌的重要免疫调节因子。 有助于在动物模型中保护免受毒性Mtb。人CD 8 T细胞杀伤细胞内Mtb，CD 8 在非人灵长类动物中的消耗导致严重的播散性结核病，而重组BCG被设计为引起 更好的CD 8 T细胞反应在小鼠中有效，临床试验已经开始。CD 8 T细胞似乎也 强制延迟！在老鼠和人身上。尽管有强烈的免疫应答，结核分枝杆菌通过以下途径逃避清除： 适应其宿主，最初的想法是基于其在吞噬体中生存并避免抗体的能力 免疫力我们现在了解到，Mtb也可以避免T细胞免疫。一个意想不到的发现， Mtb的基因组分析是编码T细胞表位的基因是高度保守的， 这被解释为意味着宿主T细胞应答有益于Mtb的存活，可能通过产生足够的 炎症促进传播。如何协调T细胞作为结核病控制工具与结核分枝杆菌 从T细胞反应中获益我们最近的数据表明，并非所有的T细胞抗原都是一样的。我们 假设TB 10是诱饵抗原。我们使用术语“诱饵”来描述其诱导强烈的CD 8 T细胞反应，识别结核分枝杆菌感染的巨噬细胞差。在免疫逃避的背景下，诱饵 抗原诱导T细胞引起炎症，但由于它们不能识别感染的细胞， 结核病感染。它们的免疫优势削弱了T细胞对其他抗原的反应，这可能是更多的 有效地提出了结核病感染的细胞和保护性免疫的目标。目标1将测试 “诱饵”假说，基于这样的想法，即如果诱饵抗原被去除，残留的T细胞应答将被抑制。 更有效地我们还将确定结核分枝杆菌如何避免采样的细胞和分子机制 MHC I的抗原。虽然Mtb逃避CD 8 T细胞免疫，但最终，CD 8促进Mtb的控制。 目的2的假设是，CD 4 T细胞的“保护性”功能是帮助CD 8 T细胞分化， 表达介导抗结核保护的功能。在没有CD 4帮助的情况下，我们预测CD 8 变得功能失调并提供次优保护。我们新的初步数据显示，“帮助”CD 8 T细胞 细胞扩增，获得效应子功能，并介导宿主保护优于“无助”的CD 8 T细胞。这里我们 我们希望确定，在原发性和继发性疾病中， 次级（即，记忆）对Mtb感染的反应。我们将定义 帮助和无助的CD 8 T细胞介导更好的保护;并确定CD 4 T细胞因子介导 帮助TB我的实验室开发了一个创新和富有成效的研究计划，旨在 了解CD 8 T细胞如何限制细菌生长以及Mtb如何击败CD 8免疫力。我们的目标是引出 保护性CD 8细胞，并将其招募到有益的反应中，作为指导疫苗开发的努力的一部分。!

Project Summary. The bacterium Mycobacterium tuberculosis (Mtb) causes more human deaths than any other pathogen. Mtb elicits strong CD8 T cell responses in people and CD8 T cells make an important contribution to protection against virulent Mtb in animal models. Human CD8 T cells kill intracellular Mtb, CD8 depletion in non-human primates leads to severe disseminated TB, and recombinant BCG designed to elicit better CD8 T cell responses is effective in mice and clinical trials have started. CD8 T cells also appear to enforce latency!in both mice and in people. Despite the vigorous immune response, Mtb evades clearance by adapting to its host, an idea originally based on its ability to survive in the phagosome and avoid antibody immunity. We are now learning that Mtb may also avoid T cell immunity. An unexpected finding from the genomic analysis of Mtb is that the genes encoding T cell epitopes are hyper-conserved, which has been interpreted to mean that the host T cell response benefits the survival of Mtb, possibly by creating sufficient inflammation to promote transmission. How does one reconcile T cells as an instrument of TB control, with Mtb benefiting from T cell responses? Our recent data suggests that not all T cell antigens are alike. We hypothesize that TB10 is a decoy antigen. We use the term ‘decoy’ to describe its ability to elicit a strong CD8 T cell response that poorly recognizes Mtb-infected macrophages. In the context of immune evasion, decoy antigens induce T cells that provoke inflammation, but as they fail to recognize infected cells, do not control Mtb infection. Their immunodominance impairs T cell responses to other antigens, which might be more efficiently presented by Mtb-infected cells and could be targets of protective immunity. Aim 1 will test the “decoy” hypothesis, based on the idea that if a decoy antigen is removed, the residual T cell response will be more effective. We will also will determine the cellular and molecular mechanisms for how Mtb avoids sampling of it antigens by MHC I. Although Mtb evades CD8 T cell immunity, ultimately, CD8 promote control of Mtb. The hypothesis of Aim 2 is that a ‘protective’ function of CD4 T cells is to help CD8 T cells differentiate and express functions that mediate protection against TB. In the absence of CD4 help, we predict that CD8s become dysfunctional and confer suboptimal protection. Our new preliminary data shows that ‘helped’ CD8 T cells expand, acquire effector function, and mediate host protection better than ‘helpless’ CD8 T cells. Here we expect to establish that helped CD8s mediate greater protection than helpless CD8s during primary and secondary (i.e., memory) responses against Mtb infection. We will define the molecular differences between helped and helpless CD8 T cells that mediate better protection; and identify the CD4 T cell factors that mediate help during TB. My lab has developed an innovative and productive research program that seeks to understand how CD8 T cells restrict bacterial growth and how Mtb defeats CD8 immunity. Our goal is to elicit protective CD8s and recruit them into beneficial responses as part of an effort to guide vaccine development. !