Inflammation plays a key role in atherogenesis and precipita-tion of atherothrombosis. Immune cells, including macrophages and T cells, infiltrate the affected vascular wall, and inflammation drives build-up of atherosclerotic plaques. 1–3 This concept of immune activation in atherosclerosis has become accepted, but specific therapy directed at inflammatory mechanisms is yet lacking. 4 T cell activation regulated by costimulatory molecules plays an important role in experimental atherogenesis. 5 Mounting evidence show that CD4+ CD28null T cells have unique capabilities that potentially promote plaque vulnerability and atherothrombosis. In this issue of Circulation Research, Dimitriu et al identify alternative costimulatory molecules that regulate CD4+ CD28null T cells and associate this mechanism with the process of plaque rupture. 6