Constitutive GITR Activation Reduces Atherosclerosis by Promoting Regulatory CD4+ T-Cell Responses
Objective—Glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) is expressed on CD4+ effector memory T cells and regulatory T cells; however, its role on these functionally opposing cell types in atherosclerosis is not fully understood.
Approach and Results—Low-density lipoprotein receptor–deficient mice (Ldlr−/−) were lethally irradiated and reconstituted with either bone marrow from B-cell–restricted Gitrl transgenic mice or from wild-type controls and fed a high-cholesterol diet for 11 weeks. Chimeric Ldlr−/− Gitrltg mice showed a profound increase in both CD4+ effector memory T cells and regulatory T cells in secondary lymphoid organs. Additionally, the number of regulatory T cells was significantly enhanced in the thymus and aorta of these mice along with increased Gitrl and Il-2 transcript levels. Atherosclerotic lesions of Ldlr−/− Gitrltg chimeras contained more total CD3+ T cells as well as Foxp3+ regulatory T cells overall, leading to significantly less severe atherosclerosis.
Conclusions—These data indicate that continuous GITR stimulation through B cell Gitrl acts protective in a mouse model of atherosclerosis by regulating the balance between regulatory and effector memory CD4+ T cells.
- Received February 8, 2016.
- Accepted July 5, 2016.
- © 2016 American Heart Association, Inc.