Lung Megakaryocytes Are A Novel Professional Antigen Presenting Cell

项目摘要 长期以来，巨核细胞（Mks）一直被认为是血小板祖细胞，但直到最近才有数据阐明 这些细胞的免疫原性作用。在我实验室的专业知识和独特工具的帮助下，我的工作表明， 肺中的Mks作为专职抗原呈递细胞（APC），而BM Mks更像非典型的 可以被诱导为具有APC样品质的APC。我们的实验室开发了独特的遗传工具来研究 Mk在T细胞应答中的作用，包括仅在Mk和血小板中缺乏MHC I或MHC II的小鼠。这 有助于理解肺Mks可以以抗原依赖性方式刺激幼稚CD 4 T细胞。肺 Mk表达MHC II和T细胞活化所必需的免疫分子，而BM Mk不表达，除非 提供免疫刺激。此外，肺Mks可以加工和呈递完整的蛋白质， 与巨噬细胞和BM Mk相比，肺和骨髓Mks都可以对多种 刺激类型，包括LPS、CpG、Poly I：C和IFNg。了解Mks APC的质量是非常重要的 这对了解许多血管炎性疾病的发病机制很重要。Mks的能力 处理和呈递抗原也可以意味着处理过的抗原可以传递给后代 血小板，这些血小板可以迅速分布在整个身体，以激活免疫细胞， 将抗原传递给它们。这一新概念可能对许多心血管疾病产生巨大影响。 可以作为治疗目标的疾病。使用我们实验室独特的MK特异性MHC I-/-和MHC II-/- 我们将展示肺Mks如何调节适应性免疫，包括Mk介导的对肺的反应。 病原体，流感。我已经建立了合作，将利用这些合作来确保问题 这个问题可以得到回答，因为我们的合作者有独特的工具，与我实验室的工具相结合， 确保我的项目成功总的来说，这些数据将使我们对Mks有一个完整的了解， 它们在适应性免疫系统中的作用。

Project Summary Megakaryocytes (Mks) have long been known to be platelet progenitors, but only recently has data illuminated an immunogenic role for these cells. Aided by the expertise and unique tools of my lab, my work shows that Mks in the lung act as professional antigen presenting cells (APCs), while the BM Mks act more like atypical APCs that can be induced to have APC-like qualities. Our lab has developed unique genetic tools to study the role of Mks in T cell responses including mice lacking MHC I or MHC II only in Mks and platelets. This has aided in understanding that lung Mks can stimulate naïve CD4 T cells in an antigen-dependent manner. Lung Mks express MHC II and immune molecules necessary for T cell activation, whereas BM Mks do not unless provided immune stimuli. Furthermore, lung Mks can process and present whole proteins and intact, live antigen with greater efficiency than macrophages and BM Mks. Both lung and BM Mks can respond to multiple types of stimuli, including LPS, CpG, Poly I:C, and IFNg. Understanding the Mks APC qualities is immensely important to understanding the pathogenesis of many vascular inflammatory diseases. The ability for the Mks to process and present antigen may also mean that the processed antigen could be passed to the progeny platelets, and these platelets could be rapidly distributed throughout the body to either activate immune cells or deliver antigen to them. This novel concept could have enormous implications for numerous cardiovascular diseases that may be therapeutically targeted. Using our lab's unique MK-specific MHC I-/- and MHC II-/- mouse we will show how lung Mks regulate adaptive immunity, including Mk, mediated responses to a lung pathogen, Influenza. I have established collaborations that will be leveraged to ensure that the questions asked can be answered, as our collaborators have unique tools, that in combination with those in my lab will help ensure the success of my project. Collectively, these data will give a complete understanding of Mks and their role in the adaptive immune system.