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 nave 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.

Public Health Relevance

My data indicates that megakaryocytes may interact directly with T cells and/or provide platelets with processed antigen as they go into circulation. This could have critically important implications on the regulation of vascular inflammatory diseases and provide new avenues for future therapeutics and is translational as we are using a specific pathogen, influenza. Due to the large number of platelets in circulation and their multiple opportunities to interact with many cell types, this could have important consequences for the host.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31HL147458-02
Application #
9959196
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mondoro, Traci
Project Start
2019-06-01
Project End
2022-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Rochester
Department
Microbiology/Immun/Virology
Type
School of Medicine & Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627