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。结核分枝杆菌 (Mtb) 造成的人类死亡人数比任何细菌都多。 Mtb 在人体中引起强烈的 CD8 T 细胞反应，并且 CD8 T 细胞发挥着重要作用。 在动物模型中，人类 CD8 T 细胞可杀死细胞内的 Mtb，CD8 有助于预防致命的 Mtb。 非人类灵长类动物的耗竭会导致严重的播散性结核病，而重组卡介苗旨在引发 更好的 CD8 T 细胞反应在小鼠中有效，并且 CD8 T 细胞的临床试验似乎也已开始。 尽管免疫反应强烈，结核分枝杆菌仍能逃避清除。 适应宿主，这个想法最初是基于其在吞噬体中生存并避开抗体的能力 我们现在了解到 Mtb 也可能避免 T 细胞免疫。 Mtb的基因组分析发现，编码T细胞表位的基因是高度保守的，这一点已被证实 解释为宿主 T 细胞反应有利于 Mtb 的生存，可能是通过产生足够的 如何协调 T 细胞作为结核病控制工具与结核分枝杆菌的关系？ 我们最近的数据表明，并非所有 T 细胞抗原都是相似的。 我们发现 TB10 是一种诱饵抗原，我们使用术语“诱饵”来描述其引发强 CD8 的能力。 T 细胞反应难以识别 Mtb 感染的巨噬细胞 在免疫逃避、诱饵的背景下。 抗原诱导 T 细胞引发炎症，但由于它们无法识别受感染的细胞，因此无法控制 Mtb 感染会损害 T 细胞对其他抗原的反应，这可能更严重。 由 Mtb 感染的细胞有效呈递，并且可能是保护性免疫的目标。目标 1 将测试 “诱饵”假说，基于这样的想法：如果诱饵抗原被去除，残留的 T 细胞反应将被抑制。 我们还将确定 Mtb 如何避免采样的细胞和分子机制。 尽管 Mtb 逃避 CD8 T 细胞免疫，但最终 CD8 会促进对 Mtb 的控制。 目标 2 的假设是 CD4 T 细胞的“保护”功能是帮助 CD8 T 细胞分化和 在没有 CD4 帮助的情况下，我们预测 CD8 会表达介导预防结核病的功能。 我们的新初步数据显示，CD8 T 变得功能失调并提供次优保护。 与“无助”的 CD8 T 细胞相比，细胞能够更好地扩增、获得效应功能并介导宿主保护。 期望确定在小学和初中阶段，有帮助的 CD8 比无助的 CD8 能提供更大的保护。 针对 Mtb 感染的次级（即记忆）反应我们将定义两者之间的分子差异。 帮助和无助的 CD8 T 细胞介导更好的保护；并识别介导 CD4 T 细胞因子； 我的实验室开发了一项创新且富有成效的研究计划，旨在 了解 CD8 T 细胞如何限制细菌生长以及 Mtb 如何击败 CD8 免疫。 保护性 CD8 并招募它们进行有益反应，作为指导疫苗开发的一部分！