Cardiovascular disease is the single largest killer of adults in North America with current therapeutics against atherosclerosis represented by drugs known as statins. Invariant Natural Killer T (iNKT) cells, T lymphocytes with qualities characterized by both innate and adaptive immune responses, have been demonstrated as key players in the progression of atherosclerosis. ABCA7, an adenosine triphosphate binding cassette transporter, has been shown to be upregulated in immune cells in response to statins. Studies have shown direct involvement of statin treatment in the regulation of the host defense system through the modulation of ABCA7. The beneficial effects of statins in atherosclerosis have been partly attributed to their immunomodulating functions. We propose that statins act on ABCA7 expression in iNKT cells, and that this alteration in ABCA7 brings about developmental and functional aberrancies in the iNKT population, which has a direct effect on the development/progression of atherosclerosis. We will first examine in detail the role ABCA7 plays in iNKT cell function and development as we have preliminary data that suggests the absence of ABCA7 negatively impacts iNKT development and function. Our first specific aim will test the hypothesis that ABCA7 modulates CD1d function in thymocytes altering the thymic developmental progression of iNKT cells. We will examine the functional capabilities of ABCA7 knockout DP thymocytes in vitro, and in vivo through the generation of mixed bone marrow chimeras. We will utilize the mixed bone marrow chimeras to also test the role of ABCA7 on iNKT in a cell intrinsic effect. The second specific aim will test the hypothesis that ABCA7 modulates CD1d function in peripheral antigen presenting cells, impacting iNKT activation. This will be done through the use of confocal microscopy where we will analyze CD1d localization and lipid antigen trafficking in ABCA7 knockout CD11c+ cells.
Specific aim three will test whether statin administration causes ABCA7-mediated changes in iNKT cell function ultimately effecting the development of atherosclerosis. We will perform adoptive transfers of ABCA7.ldlr double knockout and ldlr knockout iNKT cells, with or without statin treatment prior to transfer, into ldlr.Jalpha18 double knockout recipients for atherosclerosis studies.
Cardiovascular disease, including coronary heart disease caused by atherosclerosis, is the single largest killer of adults in North America. Approximately 13 million North Americans are taking cholesterol-lowering drugs as a preventative measure against heart disease, with the majority of these individuals taking a category of drugs known as statins. We propose to study the effect statins have on a type of T cell found in the immune system and how that effect alters the T cell's role in the development/progression of atherosclerosis.
|Nowyhed, Heba N; Huynh, Tridu R; Thomas, Graham D et al. (2015) Cutting Edge: The Orphan Nuclear Receptor Nr4a1 Regulates CD8+ T Cell Expansion and Effector Function through Direct Repression of Irf4. J Immunol 195:3515-9|
|Nowyhed, Heba N; Huynh, Tridu R; Blatchley, Amy et al. (2015) The nuclear receptor nr4a1 controls CD8 T cell development through transcriptional suppression of runx3. Sci Rep 5:9059|
|Haynes, LaTeira D; Verma, Shilpi; McDonald, Bryan et al. (2015) Cardif (MAVS) Regulates the Maturation of NK Cells. J Immunol 195:2157-67|
|Hanna, Richard N; Cekic, Caglar; Sag, Duygu et al. (2015) Patrolling monocytes control tumor metastasis to the lung. Science 350:985-90|