Targeting T Cell Costimulation to Prevent Atherothrombosis

Abstract

Inflammation plays a key role in atherogenesis and precipitation 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 Article, see p 857 To understand the implications of these novel findings, it is useful to consider that CD4+CD28null T cells, T cells deficient in the key costimulatory molecule CD28, have a distinctly different phenotype than do their CD4+CD28+ T helper cell counterparts. CD4+CD28null T cells produce cytotoxic agents that can destroy vascular endothelial cells7 and release large amounts of IFN-γ, a cytokine that robustly stimulates activity of inflammatory macrophages and promotes development of atherosclerosis.2 They are highly resistant to apoptosis and accumulate gradually throughout life.8 In addition, CD4+CD28null T cells from acute coronary syndrome (ACS) patients express a killer immunoglobulin-like receptor-variant that can elicit activation and degranulation without antigen recognition by the T cell receptor, a mechanism that might compromise …