Role of TLR2 engagement on CD4+ T cells in immunity to M. tuberculosis

TLR2 与 CD4 T 细胞的结合在结核分枝杆菌免疫中的作用

• 批准号: 8283836
• 负责人: Roxana E. Rojas
• 金额: $ 23.55万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8283836
• 关键词: Address; Adjuvant; Adjuvanticity; Adoptive Transfer; Aerosols; Animal Model; Animals; Antigen Presentation Pathway; Antigen-Presenting Cells; Antigens; Asses; Bacteria; CD4 Positive T Lymphocytes; Cell Wall; Cell physiology; Cell secretion; Cells; Chronic; Clonal Expansion; Complex; Dendritic Cells; Development; Disease; Dose; Flow Cytometry; Generations; Genes; Goals; Growth; Human; Immune; Immune response; Immune system; Immunity; Immunization; Infection; Inflammatory; Interferons; Interleukin-2; Knockout Mice; Knowledge; Ligands; Lipoproteins; Lymphoid Cell; Measures; Memory; Modeling; Mouse Strains; Mus; Mycobacterium tuberculosis; Myeloid Cells; Pathway interactions; Pattern; Pattern recognition receptor; Population; Regulation; Reporting; Research Project Grants; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Transduction; System; T cell response; T-Cell Activation; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; Testing; Toll-Like Receptor 2; Transgenic Organisms; Tuberculosis; Tuberculosis Vaccines; Vaccine Adjuvant; acquired immunity; cell type; chemokine; cytokine; design; improved; in vivo; in vivo Model; innate immune function; killings; macrophage; memory recall; microbial; mycobacterial; novel; novel vaccines; pathogen; prevent; receptor; response; trafficking; vaccination against tuberculosis

DESCRIPTION (provided by applicant): In addition to recognizing antigens (Ags) via the T cell receptor (TCR), CD4+T cells can recognize microbial patterns through pattern recognition receptors (PRRs). Human CD4+ T cells can directly recognize mycobacterial lipoproteins via Toll-like receptor 2 (TLR2). In combination with TCR triggering, TLR2 engagement induces CD4+T cell proliferation and secretion of IL-2 and IFN-¿ . The role of TLR2 expressed on CD4+ T cells in T cell activation/differentiation in vivo and its impact on immune responses to M. tuberculosis (Mtb) remains unexplored. One major challenge in understanding T cell TLR2 role in Mtb infection is the lack of adequate animal models to isolate the effects of TLR2 signaling in lymphoid cells from those triggered by TLR2 signaling in myeloid cells. Considering that TLR2 ligands are major components of the Mtb cell wall and traffic inside and outside the infected macrophages, it is important to establish their effects in different immune cells in vivo. This proposal is aimed at defining the role of TLR2 ligand recognition by CD4+ T cells in Mtb infection and after immunization with Mtb antigens using novel in vivo models. We hypothesize that direct recognition of mycobacterial TLR2 ligands by CD4+T cells: a) generates signals that up-regulate Th1 and multifunctional CD4+T cell responses in Mtb infection in vivo; b) results in enhanced immune protection against Mtb; c) can be targeted by vaccine adjuvants to generate stronger memory and recall responses to Mtb. These hypotheses will be tested with two specific Aims: Aim 1. Establish the role TLR2 expressed on CD4+T cells in the immune response to Mtb infection. Aim 2. Determine the impact of mycobacterial TLR2 ligand recognition by CD4+T cells in generation of memory and recall responses to Mtb antigens. To test our hypotheses, we will correlate TLR2 expression on CD4+ T cells with T cell expansion/effector function/differentiation in vivo in an Mtb aerosol infection model. To asses the effect of TLR2 deficiency in CD4+T cells on immune responses to Mtb infection and to immunization we will use two approaches: a) adoptive transfer of Mtb specific-TCR transgenic (Tg) CD4+T cells isolated from Tlr2+/- or from Tlr2-/- mice; b) generation of new conditional knockout mouse strain where TLR2 is selectively deleted in T cells (Tlr2flox/flox x CD4-Cre mice= Tlr2¿T mice). Our long-term goal is to understand mechanisms that protect against Mtb infection and/or prevent progression to TB disease and apply this knowledge to development of new vaccines. Our immediate goal is to establish the role of TLR2 ligand recognition by CD4+T cells in immune defense against Mtb. Also, we will determine the potential of targeting CD4+T cell expressed-TLR2 with vaccine adjuvants to improve recall responses and protection. In addition to expanding our understanding of the host-pathogen interaction in Mtb infection, this research project may provide new targets for adjuvants, i.e. CD4+T cell TLR2. PUBLIC HEALTH RELEVANCE: Mycobacterium tuberculosis (Mtb), the bacteria that causes tuberculosis (TB), infects one-third of the world population and kills more than 1.5 million each year. Development of new vaccines required to prevent TB relies on a better understanding of the immune response to Mtb infection. This project investigates the role of receptors expressed on immune cells (T cells) in mechanisms of protection against Mtb.

描述（由应用提供）：除了通过T细胞受体（TCR）识别抗原（AGS）外，CD4+T细胞还可以通过模式识别受体（PRR）识别微生物模式。人CD4+ T细胞可以通过Toll样受体2（TLR2）直接识别分枝杆菌脂蛋白。结合TCR触发，TLR2参与度诱导CD4+T细胞的增殖以及IL-2和IFN- - 的分泌。 TLR2在CD4+ T细胞中表达的TLR2在体内T细胞激活/分化中的作用及其对结核分枝杆菌（MTB）免疫反应的影响仍然出乎意料。理解T细胞TLR2在MTB感染中的作用的一个主要挑战是缺乏足够的动物模型来隔离TLR2信号在淋巴样细胞中的作用与髓样细胞中TLR2信号传导触发的动物模型。考虑到TLR2配体是MTB细胞壁的主要组成部分，并且在感染的巨噬细胞内部和外部交通，因此在体内建立它们的影响很重要。该建议旨在使用新颖的体内模型来定义CD4+ T细胞在MTB感染中和MTB抗原免疫抑制后TLR2配体识别的作用。我们假设通过CD4+T细胞对分枝杆菌TLR2配体的直接识别：a）产生信号，表明在体内MTB感染中会导致TH1和多功能CD4+T细胞反应； b）导致对MTB的免疫保护增强； c）疫苗调节器可以针对目标，以产生更强的记忆并回忆对MTB的反应。这些假设将以两个特定的目的进行检验：目标1。在免疫反应中，在对MTB感染的免疫反应中，在CD4+T细胞上表达的作用TLR2。 AIM 2。确定CD4+T细胞识别分枝杆菌TLR2配体在产生记忆和回忆对MTB抗原的反应中的影响。为了检验我们的假设，我们将在MTB气溶胶感染模型中将CD4+ T细胞上的TLR2表达与T细胞膨胀/效应函数/分化相关联。为了评估CD4+T细胞中TLR2缺乏症对MTB感染的免疫复杂和免疫抑制的影响，我们将使用两种方法：a）MTB特异性TCR转基因（TG）CD4+T细胞的适应性转移，与TLR2 +/-或从TLR2 - / - / - / - / - - / - - - / - 小米中分离出来； b）在T细胞中选择性删除TLR2的新条件敲除小鼠应变（TLR2Flox/Flox X CD4-CRE小鼠=TLR2¿T小鼠）。我们的长期目标是了解预防MTB感染和/或防止TB疾病发展的机制，并将这种知识应用于新疫苗的发展。我们的近期目标是确定CD4+T细胞在针对MTB的免疫防御中识别TLR2配体识别的作用。此外，我们将确定针对用疫苗调节器表达TLR2的CD4+T细胞以改善回忆反应和保护的潜力。除了扩展我们对MTB感染中宿主 - 病原体相互作用的理解外，该研究项目还可以为调节器提供新的目标，即CD4+T细胞TLR2。 公共卫生相关性：结核分枝杆菌（MTB），导致结核病（TB）的细菌（TB），感染世界人口的三分之一，每年杀死150万以上。防止结核病所需的新疫苗的开发取决于对MTB感染的免疫响应的更好理解。该项目研究了对免疫细胞（T细胞）对MTB的保护机理中表达的受体的作用。