Regulation of CD8+ T cell immunity to tuberculosis (pending title)

CD8 T 细胞对结核病免疫的调节（待定标题）

基本信息

批准号：
8711279
负责人：
SAMUEL M BEHAR
金额：
$ 64.78万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-02 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8711279
关键词：
AIDS/HIV problem Abbreviations Address Affect Affinity Animal Model Animals Antigen-Presenting Cells Avidity Biological Markers Bone Marrow Bronchoalveolar Lavage CD4 Positive T Lymphocytes CD8B1 gene Cell Line Cells Chronic Clinical Colony-forming units Data Dendritic Cells Development Disease Disease Progression Disease Resistance Drug resistance in tuberculosis Effectiveness Effector Cell Epidemic Epitopes Evaluation Future Gene Expression Genes Genetic Genetic Transcription Goals Grant Green Fluorescent Proteins Growth Host resistance Human Immune response Immune system Immunity Immunodominant Epitopes Infection Infection Control Inflammatory Interferon Type II Interferons Interleukin-10 Interleukin-12 Interleukin-2 Interleukins Knock-out Lead Lesion Life Lung Major Histocompatibility Complex Measures Mediating Mediator of activation protein Memory Modeling Molecular Monoclonal Antibodies Mononuclear Multi-Drug Resistance Mus Mycobacterium tuberculosis Pathway interactions Phenotype Population Pulmonary Tuberculosis Regulation Regulatory Pathway Relative (related person)Research Research Personnel Review Literature Role Scourge Series Signal Transduction Sterilization T cell response T memory cell T-Cell Activation T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets TNF gene Toll-like receptors Tuberculosis Tumor Necrosis Factor-alpha Uncertainty Vaccinated Vaccines Virulent bactericide base combat exhaust global health innovation insight interleukin-12 receptor intraperitoneal lymph nodes macrophage pathogen perforin prevent public health relevance recombinase tool tuberculosis immunity vaccination strategy vaccine development

项目摘要

DESCRIPTION (provided by applicant): The continuing HIV/AIDS epidemic and the spread of multi-drug resistant Mycobacterium tuberculosis (Mtb) has perpetuated an epidemic of tuberculosis in populations around the world. While BCG is used universally as a vaccine, it is not effective in preventing pulmonary tuberculosis. To combat this ongoing worldwide scourge, vaccine development for tuberculosis is a priority. Convincing experimental evidence exists that CD8+ T cells are required for optimal immunity to tuberculosis in mice and other experimental animals. How T cell mediate protection is incompletely understood, and the old paradigm that IFN-g is "end-all" and "be- all" of T cell effector function is being dismantled. Importantly, ther is a huge, clinically important paradox - namely that T cells are crucial to immunity against TB, but the one mediator of protection, IFN-g, does not predict or correlate with protection against disease. Therefore, there must be other correlates of protection. Innovation: We have four retrogenic (Rg) mouse lines, each expressing a different TCR that recognizes the immunodominant epitope TB104-11. Interestingly, these different TCRs vary in their affinity and potential to mediate protection against virulent Mtb. These Rg make feasible experimental strategies to define the molecular basis for how CD8+ T cells mediate protection. Aims: Overview: While there is little doubt that CD8+ T cells make an important contribution to protection against TB, the effector function(s) that inhibit Mtb growth are largely unknown. In Aim 1, we will determine the different effector molecules that contribute to the protection mediated by CD8+ T cells during Mtb infection. Aim 2 will focus on the basic signals that lead to T cell activation and determine how they impact the expression of protective effector functions. These include 1) strength of TCR signaling; 2) the role of CD4+ T cell help and IL-2; and 3) the inflammatory Signal 3. Much of what we know about T cell immunity to Mtb is from studies of primary infection. A more comprehensive understanding of memory T cell responses is needed for vaccine development. We observe a loss of the memory T cells following rechallenge. Thus, an important question is whether vaccine-elicited T cells have a durable phenotype without reversion to ineffectual T cells. Therefore, in Aim 3 we will address whether the primary and secondary CD8+ T cell responses differ in the effector pathways utilized and how they are regulated. Summary: Mtb is a successful pathogen that persists in humans despite a robust immune response. We have three goals: 1) define the mechanisms used by CD8+ T cells to restrict bacterial replication; 2) determine how effector mechanisms are regulated; and 3) determine whether primary and secondary CD8+ T cell responses are regulated differently. Our answers will not only illuminate how T cells mediate protection, but we expect to validate protective pathways that can function as biomarkers to guide vaccines development and evaluation.

描述（由申请人提供）：持续的艾滋病毒/艾滋病流行和多药抗性分枝杆菌结核病（MTB）的传播使世界各地人群中的结核病流行永久存在。尽管BCG普遍用作疫苗，但它在预防肺结核方面无效。为了打击这种持续的全球祸害，重中之重是结核病的疫苗开发。有说服力的实验证据存在CD8+ T细胞对小鼠和其他实验动物的结核病的最佳免疫需要。 T细胞如何介导保护是不完全理解的，而旧的IFN-G为“终止”和“ be-be”的旧范式正在拆除。重要的是，这是一个巨大的，临床上重要的悖论 - 即T细胞对抗结核的免疫力至关重要，但是一个保护介质IFN -G并未预测或与保护疾病的保护。因此，必须有其他保护的关联。创新：我们有四种后源性（RG）小鼠系，每种表达了一种识别免疫降低表位TB104-11的不同TCR。有趣的是，这些不同的TCR在其亲和力方面有所不同，并且有可能调解对有毒MTB的保护。这些RG制定了可行的实验策略，以定义CD8+ T细胞如何介导保护的分子基础。目的：概述：毫无疑问，CD8+ T细胞对防止TB的保护做出了重要贡献，但抑制MTB生长的效应子功能在很大程度上是未知的。在AIM 1中，我们将确定在MTB感染期间由CD8+ T细胞介导的保护的不同效应分子。 AIM 2将重点放在导致T细胞激活的基本信号上，并确定它们如何影响保护效应子函数的表达。其中包括1）TCR信号的强度； 2）CD4+ T细胞帮助和IL-2的作用； 3）炎症信号3。我们对T细胞对MTB的免疫的了解大部分来自原发性感染的研究。疫苗开发需要更全面地了解记忆T细胞反应。我们观察到恢复后记忆T细胞的丧失。因此，一个重要的问题是，疫苗吸收的T细胞是否具有耐用的表型，而无需重新恢复到无效的T细胞。因此，在AIM 3中，我们将解决主要和次级CD8+ T细胞响应在使用的效应途径以及如何调节它们的情况下是否有所不同。摘要：MTB是一种成功的病原体，尽管有强大的免疫反应，但仍在人类中持续存在。我们有三个目标：1）定义CD8+ T细胞用来限制细菌复制的机制； 2）确定如何调节效应机制； 3）确定原发性CD8+ T细胞反应的调节是否不同。我们的答案不仅会阐明T细胞如何介导保护，而且我们希望验证可以用作生物标志物来指导疫苗开发和评估的保护途径。