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）

• 批准号: 8550320
• 负责人: SAMUEL M BEHAR
• 金额: $ 60.56万
• 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 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8550320
• 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

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HIV/AIDS流行和耐多药结核分枝杆菌（Mtb）的传播使结核病在世界各地的人群中持续流行。虽然卡介苗被普遍用作疫苗，但它对预防肺结核并不有效。为了与这一持续的世界性祸害作斗争，开发结核病疫苗是一个优先事项。令人信服的实验证据表明，小鼠和其他实验动物对结核病的最佳免疫力需要CD 8 + T细胞。T细胞是如何介导保护作用的还不完全清楚，IFN-g是T细胞效应功能的“最终”和“全部”的旧范式正在被拆除。重要的是，有一个巨大的，临床上重要的悖论-即T细胞对结核病的免疫至关重要，但保护的一种介质IFN-g并不能预测或与疾病的保护相关。因此，必须有其他相关的保护。创新：我们有四个逆转录（Rg）小鼠品系，每个品系表达不同的TCR，识别免疫显性表位TB 104 -11。有趣的是，这些不同的TCR在其亲和力和介导针对毒性Mtb的保护的潜力方面不同。这些Rg使可行的实验策略，以确定CD 8 + T细胞如何介导保护的分子基础。目的：概述：虽然CD 8 + T细胞对预防TB做出重要贡献是毫无疑问的，但抑制Mtb生长的效应子功能在很大程度上是未知的。在目的1中，我们将确定在Mtb感染期间有助于由CD 8 + T细胞介导的保护的不同效应分子。目标2将重点关注导致T细胞活化的基本信号，并确定它们如何影响保护性效应子功能的表达。这些包括1）TCR信号传导的强度; 2）CD 4 + T细胞辅助和IL-2的作用;和3）炎性信号3。我们对结核分枝杆菌的T细胞免疫的了解大部分来自原发感染的研究。疫苗开发需要更全面地了解记忆T细胞反应。我们观察到再激发后记忆T细胞的损失。因此，一个重要的问题是疫苗诱导的T细胞是否具有持久的表型而不逆转为无效的T细胞。因此，在目标3中，我们将讨论初级和次级CD 8 + T细胞应答是否在所利用的效应子途径中不同以及它们是如何调节的。摘要：结核分枝杆菌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）确定CD 8 + T细胞限制细菌复制的机制; 2）确定效应机制如何调节; 3）确定初级和次级CD 8 + T细胞应答是否受到不同的调节。我们的答案不仅将阐明T细胞如何介导保护，而且我们希望验证可以作为生物标志物指导疫苗开发和评估的保护途径。