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.