Atherosclerosis is a complex inflammatory disease characterized by the retention and modification of lipids within the vascular wall. Recently, the role of distinct T cell subsets in the development of atherosclerosis has been evaluated. One particular T cell subsets recognizes lipid antigens presented by CD1 family of antigen presenting molecules. In humans, this family consists of the group 1 CD1 molecules CD1a, b, and c, and the group 2 molecule CD1d. Mice lack group 1 CD1, but express CD1d. The unique binding specificity of CD1 suggests a potential role for the CD1 molecules in the presentation of modified lipids to T cells involved in atherogenesis. Indeed, CD1d-restricted invariant NKT cells have been shown to play a proatherogenic role in murine models of atherosclerosis. Moreover, elevated expression levels of group 1 CD1 have been observed in atherosclerotic plaques found in humans, and group 1 CD1-restricted T cells can be activated by macrophage-derived foam cells in vitro. While these findings suggest that group 1 CD1 molecules and their cognate T cells contribute to the pathogenesis of this disease, the functional role of group 1 CD1-restricted T cells in atherosclerosis has not been directly studied due to the lack of a suitable animal model. To overcome this limitation, my lab has generated transgenic mouse models that express both the human group 1 CD1 molecules and group 1 CD1-specific T cell receptors. In this study, we propose to utilize these novel transgenic mouse models to test the hypothesis that group 1 CD1-restricted T cells contribute to atherogenesis.
In Aim 1, we propose to determine the overall contribution of group 1 CD1-restricted responses to atherogenesis in a diet-induced atherosclerosis model and to investigate the mechanisms by which group 1 CD1-restricted autoreactive T cells contribute to disease pathogenesis.
In Aim 2, we propose to examine whether hyperlipidemic conditions associated with atherosclerosis affect the activation and function of group 1 CD1-restricted T cells, as well as the mechanisms mediating such effects. Collectively, these studies will lead to a better understanding of how group 1 CD1-restricted autoreactive T cells contribute to atherosclerosis and whether they can be manipulated to modulate the progression of the disease.

Public Health Relevance

Atherosclerosis is the leading cause of morbidity and mortality in the United States. Dyslipidemia has been shown to be an important risk factor for atherosclerosis, highlighting a potential role of lipid antigen-specific T cells in atherogenesis. This study proposes to examine the role of human group 1 CD1-autoreactive T cells, a novel subset of self lipid antigen-specific T cells, in atherosclerosis. Although mice do not normally express group 1 CD1 molecules, we have developed transgenic mouse models that express both human group 1 CD1 molecules and group 1 CD1-specific T cell receptors, uniquely suited for this study. We anticipate that these studies will provide insight into the pathogenesis of atherosclerosis as well as other lipid-related immune-mediated diseases, and may lead to the development of new strategies for therapeutic intervention and prevention of these diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL112186-02
Application #
8603279
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Hasan, Ahmed AK
Project Start
2013-02-01
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
$173,813
Indirect Cost
$61,313
Name
Northwestern University at Chicago
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611