Constitutive GITR activation reduces atherosclerosis by promoting regulatory CD4⁺ T-Cell responses-brief report

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^-/- Gitrl^tg 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^-/- Gitrl^tg 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.