TRAIL-expressing CD4+ T cells trigger apoptosis of vascular smooth muscle cells (red) in atherosclerotic plaques

The narrowing of arteries is a natural process caused by the gradual deposition of fat and cholesterol into artery walls. The buildup of arterial plaques (atherosclerosis) is a long-term process that, for some, culminates in acute coronary syndromes (ACSs) such as heart attack and cardiac arrest. These acute attacks are caused by the sudden rupture of atherosclerotic plaques—an event that may happen more readily in some individuals than in others.

Plaques that contain immune cells such as macrophages and T cells are the most vulnerable to rupture, although the mechanism behind this observation is not well understood. Now, Sato and colleagues show that CD4⁺ T cells that infiltrate atherosclerotic plaques trigger the death of vascular smooth muscle cells (VSMCs), a process proposed to destabilize the plaques.

The plaque-infiltrating T cells expressed high levels of TRAIL, a death receptor normally used by T cells and NK cells to destroy cancerous cells. The expression of this receptor was required for T cells to induce apoptosis in VSMCs (which expressed the TRAIL receptor DR5) both in vitro and in vivo. CD4⁺ T cells from patients with ACS expressed higher levels of TRAIL when activated and were more adept at triggering VSMC apoptosis in vitro compared with T cells from healthy individuals, possibly explaining why these individuals developed acute disease while others were spared. What causes plaque-residing VSMCs to express DR5 and why T cells infiltrate the plaques in some individuals is not yet known.

These results demonstrate that the TRAIL pathway—previously thought to induce death only in cancer cells—can also trigger apoptosis in nontransformed cells. A recombinant form of TRAIL is currently in clinical trials for the treatment of certain cancers, a therapeutic approach that might need reevaluation in light of its potential negative effects on patients with atherosclerosis.