MTB directly regulates human CD4+ T cell activation

描述(由申请者提供)：该指导职业发展奖中建议的项目将提供所需的培训和经验，以实现我的长期职业目标，成为一名独立的医生-科学家，进行翻译研究，探索人类免疫系统和微生物病原体之间的动态相互作用。我的职业发展计划将研究生水平的课程工作与我的合作导师和咨询委员会的仔细监督结合在一起，以确保为我提供必要的科学背景和指导，以便在我的职业生涯中通过合理的项目设计、执行和数据解释来产生假设驱动的研究。凯斯西储大学的学术和科学界将提供最先进的环境资源来支持我的职业目标，并提供必要的保护时间，让我通过教学课程工作、教育研讨会和会议，以及追求本提案中包括的研究目标，发展我作为医生-科学家的技能。在这项申请下提出的“结核分枝杆菌直接调节人类CD4+T细胞活化”的项目提出了一种假设，即结核分枝杆菌(MTB)感染细胞释放的分子直接与人类CD4+T细胞相互作用，导致T细胞活化的共刺激和上调。支持这一假说的初步数据表明，在T细胞受体刺激后，MTB分子直接上调人类CD4+T细胞的激活。结核分枝杆菌和人类CD4+T细胞之间的这种相互作用可能会影响宿主对病原体产生有效的适应性免疫反应的能力。这些观察表明，人类CD4+T细胞利用模式识别受体来感知和响应外来物质，探索这一假说将促进对病原体如何与人类免疫反应相互作用和调节的理解。除了确定已识别的结核分枝杆菌分子与CD4+T细胞之间相互作用的后果，以及介导这种相互作用的受体外，该项目还将探索CD4+T细胞对已识别分子的反应差异是否会影响宿主对结核病的易感性。相关性(见说明)：这项研究将扩大对人类对感染结核杆菌的免疫反应的理解，并有助于开发更好的结核杆菌疫苗。通过推进人类免疫系统的基本组成部分，如T细胞如何与外来病原体相互作用的知识，这项研究将有助于开发针对广泛病原体的新型免疫疗法。

DESCRIPTION (provided by applicant): The projects proposed in this mentored career development award will provide the training and experience required to reach my long term career goal to become an independent physician-scientist conducting translational research that explores the dynamic interaction between the human immune system and microbial pathogens. My career development plan combines graduate level course work with careful oversight by my co-mentors and advisory committee to ensure I am provided with the scientific background and guidance necessary to produce hypothesis driven research with rational project design, execution, and data interpretation throughout my career. The academic and scientific community of Case Western Reserve University will provide state-of-the-art environmental resources to support my career goals, as well as the necessary protected time to allow development of my skills as a physician-scientist through didactic course work, educational seminars and conferences, and pursuit of the research aims included in this proposal. The projects proposed under this application "MTB directly regulates human CD4+ T cell activation" introduce the hypothesis that molecules released by cells infected with Mycobacterium tuberculosis (MTB), directly interact with human CD4+ T cells leading to costimulation and upregulation of T cell activation. The preliminary data supporting this hypothesis demonstrate molecules from MTB directly upregulate human CD4+ T cell activation following T cell receptor stimulation. This interaction between MTB and human CD4+ T cells may influence the host's ability to mount an effective adaptive immune response against the pathogen. These observations suggest human CD4+ T cells utilize pattern-recognition-receptors to sense and respond to foreign material, and exploration of this hypothesis will advance the understanding of how pathogens interact with and modulate the human immune response. In addition to defining the consequences of the interaction between the identified MTB molecules and CD4+ T cells, and the receptor mediating the interaction, this project will explore if differences in CD4+ T cell responses to the identified molecules Influence host susceptibility to tuberculosis. RELEVANCE (See instructions): This research will expand the understanding of the human immune response to infection with MTB and contribute to the development of a superior MTB vaccine. By advancing knowledge of how essential components of the human immune system such as T cells interact with a foreign pathogen, this research will contribute to development of novel immunotherapies for a broad range of pathogens.