Regulation of CD8+ T cell immunity to tuberculosis

CD8 T 细胞对结核病免疫的调节

• 批准号: 9918239
• 负责人: SAMUEL M BEHAR
• 金额: $ 70.46万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-02 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918239
• 关键词: AIDS/HIV problem; Adult; Affect; Animal Model; Antibiotics; Antibodies; Antigen Presentation; Antigens; Antimicrobial Resistance; Area; Bacillus; Bacteria; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Cells; Cessation of life; China; Clinical; Clinical Trials; Cytoprotection; Data; Diabetes Mellitus; Disease; Drug resistance in tuberculosis; Effectiveness; Effector Cell; Epidemic; Epitopes; Frequencies; Funding; Genes; Genetic; Genetic Polymorphism; Genomics; Goals; Grant; Growth; Human; Immune Evasion; Immune response; Immune system; Immunity; Impairment; India; Infection; Infection Control; Inflammation; Interleukin-15; Learning; MHC Class II Genes; MHC antigen; Mediating; Memory; Modeling; Molecular; Multi-Drug Resistance; Mus; Mycobacterium bovis; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Pathway interactions; Phagosomes; Prevalence; Proteins; Pulmonary Tuberculosis; Regulation; Research; Research Proposals; Residual state; Sampling; T cell differentiation; T cell response; T-Lymphocyte; T-Lymphocyte Epitopes; TCF Transcription Factor; Testing; Tuberculosis; Vaccination; Vaccine Design; Vaccines; Virulent; Work; base; cell killing; design; emerging antimicrobial resistance; global health; improved; innovation; instrument; macrophage; nonhuman primate; pathogen; prevent; programs; rBCG; recruit; response; tool; transmission process; tuberculosis immunity; vaccine development; vaccine evaluation

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. !

项目摘要。细菌结核分枝杆菌（MTB）造成人类死亡更多 其他病原体。 MTB在人和CD8 T细胞中引起强烈的CD8 T细胞反应使得 在动物模型中保护有毒MTB的保护。人CD8 T细胞杀死细胞内MTB，CD8 非人类素数的耗竭导致严重的散布结核病，重组BCG旨在引起 更好的CD8 T细胞反应在小鼠中有效，并且已经开始临床试验。 CD8 T细胞似乎也 执行延迟！在老鼠和人中。尽管有剧烈的免疫反应，MTB还是通过 适应宿主，这个想法最初是基于其在吞噬体中生存的能力并避免抗体 免疫。我们现在了解到MTB也可能避免T细胞免疫。从 MTB的基因组分析是，编码T细胞表位的基因是过度保存的，这一直是 被解释为意味着宿主T细胞响应使MTB的生存受益，这可能是通过创建足够的 炎症以促进传播。一个人如何用MTB调和T细胞作为TB对照的仪器 受益于T细胞反应？我们最近的数据表明，并非所有T细胞抗原都是相同的。我们 假设TB10是一种诱饵抗原。我们使用“诱饵”一词来描述其引发强大CD8的能力 T细胞反应很差，识别MTB感染的巨噬细胞。在免疫避难所的背景下，诱饵 抗原诱导T细胞引起感染，但由于无法识别感染细胞，因此不控制 MTB感染。它们的免疫主导会损害T细胞对其他抗原的反应，这可能更多 由MTB感染的细胞有效地提出，可能是保护性免疫的靶标。 AIM 1将测试 “诱饵”假设，基于以下想法：如果去除诱饵抗原，残留的T细胞反应将为 更有效。我们还将确定MTB如何避免采样的细胞和分子机制 MHC I的IT抗原中的IT抗原，尽管MTB逃避CD8 T细胞免疫学，但最终CD8促进了MTB的控制。 AIM 2的假设是CD4 T细胞的“保护性”功能是帮助CD8 T细胞区分和 表达介导对结核病保护的功能。在没有CD4帮助的情况下，我们预测CD8 变得功能失调和会议次优的保护。我们的新初步数据表明，“帮助” CD8 T 细胞比“无助” CD8 T细胞更好地扩展，获取效应子功能并更好地介导宿主保护。我们在这里 期望确定在初级和 二次（即记忆）反应针对MTB感染。我们将定义分子差异 帮助和无助的CD8 T细胞，介导更好的保护；并确定介导的CD4 T细胞因子 在结核病期间帮助。我的实验室制定了一项创新和产品研究计划，试图 了解CD8 T细胞如何限制细菌生长以及MTB如何击败CD8免疫。我们的目标是引起 保护CD8并将其招募成有益的反应，以此作为指导疫苗开发的努力的一部分。