T cell memory to TB in the lung

T细胞对肺部结核病的记忆

• 批准号: 7556356
• 负责人: ANDREA M COOPER
• 金额: $ 44.5万
• 依托单位: TRUDEAU INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7556356
• 关键词: AG 85; Address; Adjuvant; Aerosols; Antibodies; Antigens; Bone Marrow; Boxing; Breeding; CD4 Positive T Lymphocytes; Cells; Chimera organism; Collaborations; Data; Development; Ensure; Environment; Epitopes; Flow Cytometry; Generations; Goals; Grant; Growth; Human; Immune response; Immunity; Incidence; Infection; Interferons; Interleukin-1; Interleukin-12; Interleukin-17; Interleukin-6; Interleukins; Investigation; Life; Location; Longevity; Lung; Lymphoid; Mediating; Memory; Modeling; Mouse Strains; Mus; Mycobacterium tuberculosis; Myeloid Cells; Nature; Peptides; Phase; Population; Principal Investigator; Public Health; Reagent; Recombinant Chemokine; Recruitment Activity; Reporter; Research Personnel; Risk; Role; Route; T memory cell; T-Cell Receptor; T-Lymphocyte; Techniques; Testing; Transgenic Mice; Transgenic Organisms; Tuberculosis; Vaccinated; Vaccination; Vaccine Design; Vaccines; Vertebrates; Work; animal facility; base; cell type; chemokine; cytokine; improved; interleukin-22; interleukin-23; macrophage; memory CD4 T lymphocyte; memory recall; novel; peptide based vaccine; programs; protective effect; public health relevance; research study; response

DESCRIPTION (provided by applicant): Tuberculosis (TB) is a serious public health issue and rational development of effective vaccines requires that we understand the cellular mechanisms mediating protective immunity; this is the focus of the current proposal. We show here that while protective memory can be effective against Mycobacterium tuberculosis (Mtb) it is delayed when the challenge route mimics natural exposure. Crucially, this delay allows bacterial growth in the lungs even of vaccinated mice. Clearly, accelerating the memory response to result in earlier suppression of bacterial growth is an important goal. In this regard we have identified a novel population of memory cells that produces interleukin (IL)-17, resides in the lung, responds quickly to aerosol infection and which is required for protective memory. In the absence of this IL-17 memory population, the interferon (IFN)-? memory response is lost. The IL-17-producing memory cells are IL-23 dependent and are associated with an accelerated chemokine response. These data prompted the hypothesis that IL-17-producing memory cells recruit IFN-? producing memory cells. If this is true then the IL-17-producing memory population is a novel prime target for vaccination. Specifically, manipulating the response of these cells could overcome the delay in the protective memory that limits the efficacy of current vaccine strategies. In this proposal we will test the following working model: Vaccine-induced, IL-23 dependent, IL-17-producing memory CD4+ T cells resident in the lung respond to Mtb, produce IL-17, trigger the local expression of chemokines which attract IFN-?-producing memory CD4+ T cells. These IFN-? memory CD4+ T cells then activate myeloid cells to halt Mtb growth. The model will be tested using three aims: Aim One: To determine the factors required for induction of protective memory T cells. The requirement for IL-23 in proliferation, survival and phenotypic development of IL-17-producing memory cells capable of populating the lung will be determined. Aim Two: To determine whether IL-17 mediates vaccine-induced protection by recruiting IFN-? producing CD4+ T cells. We will determine whether IL-17-induced chemokine responses and accelerated accumulation of IFN-?-producing memory cells are essential for vaccine-induced protection. Aim Three: To determine whether modulating the IL-17 memory response in the lung can increase protection. We will determine whether increasing the IL-17 population in the lung improves vaccine-induced protection. Proof of this working model will provide a basis for rational vaccine design and investigation of the role of these cells in humans. PUBLIC HEALTH RELEVANCE: We know too little about how the vaccine-induced protective response to tuberculosis works. If we do not know how the response works it is difficult to improve upon it. By investigating the way the response works we have identified new cell types that can be targeted by vaccination. These new cell types may improve the protective effect of vaccines and thereby reduce the incidence of tuberculosis in the world. This will have a significant impact in worldwide public health.

描述（由申请人提供）：结核病（TB）是一个严重的公共卫生问题，有效疫苗的合理发展要求我们了解介导保护性免疫的细胞机制；这是当前建议的重点。我们在这里表明，尽管保护性记忆可以有效地抵抗结核分枝杆菌（MTB），但当挑战路线模仿自然暴露时，它会延迟。至关重要的是，这种延迟允许肺部甚至接种疫苗的小鼠的细菌生长。显然，加速记忆反应以导致较早抑制细菌生长是一个重要目标。在这方面，我们已经确定了产生白介素（IL）-17的新型记忆细胞种群，它存在于肺部，对气溶胶感染迅速反应，这是保护性记忆所必需的。在没有IL-17记忆群的情况下，干扰素（IFN） - ？内存响应丢失。产生IL-17的记忆细胞是IL-23依赖性的，并且与加速的趋化因子反应有关。这些数据提出了这样一个假设，即产生IL-17的记忆细胞募集了IFN-？产生记忆单元。如果这是正确的，那么产生IL-17的记忆群是疫苗接种的新型主要目标。具体而言，操纵这些细胞的响应可能会克服限制当前疫苗策略功效的保护记忆的延迟。在该提案中，我们将测试以下工作模型：疫苗诱导的IL-23依赖性，IL-17产生的记忆CD4+ T细胞驻留在肺中，对MTB产生响应，产生IL-17，触发吸引吸引的趋化因子的局部表达IFN - ？ - 产生内存CD4+ T细胞。这些ifn-？记忆CD4+ T细胞随后激活髓样细胞以阻止MTB生长。该模型将使用三个目标进行测试：目标：确定诱导保护性记忆T细胞所需的因素。将确定IL-23在增殖，生存和表型发育中产生肺部填充肺的生存和表型发育的需求。目标二：确定IL-17是否通过招募IFN-介导疫苗诱导的保护？产生CD4+ T细胞。我们将确定IL-17诱导的趋化因子反应和IFN产生记忆细胞的加速积累是否对于疫苗诱导的保护至关重要。目标三：确定在肺中调节IL-17记忆反应是否可以增加保护。我们将确定增加肺中IL-17人群是否可以改善疫苗引起的保护。该工作模型的证明将为这些细胞在人类中的作用提供理性疫苗设计和研究提供基础。 公共卫生相关性：我们对疫苗诱导的对结核病的保护性反应的了解程度很少。如果我们不知道响应是如何起作用的，那么很难改善它。通过研究响应的工作方式，我们已经确定了可以通过疫苗接种靶向的新细胞类型。这些新的细胞类型可以改善疫苗的保护作用，从而减少世界上结核病的发生率。这将对全球公共卫生产生重大影响。