Editors' ChoiceHeart Disease

T Cells Gone Bad in Heart Disease

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Science Translational Medicine  04 Apr 2012:
Vol. 4, Issue 128, pp. 128ec56
DOI: 10.1126/scitranslmed.3004063

The immune system is usually the good guy—ably keeping out invaders, preventing disease, and orchestrating healing—but it also has a dark side. In heart disease, the immune system is a key player that drives the development of artery-clogging plaques. Some of these plaques act like time bombs—spontaneously rupturing and causing heart attack and stroke. What causes such an event is a mystery; how to prevent rupture is a critical question in cardiovascular medicine. In a recent study, Dumitriu et al. discovered new information about a class of immune cells associated with ruptured plaques.

Acute coronary syndrome (ACS) is characterized by heart attack or unstable chest pain—both of which are a result of rupturing plaques in the vessels of the heart. Previous work revealed that relative to healthy patients or those with stable chest pain, ACS patients exhibit high levels of a specific type of T cells, termed CD4+CD28null T cells, which accumulate in ruptured plaques. Such lymphocytes lack the costimulatory receptor CD28 and are inflammatory and cytotoxic. T cell costimulation is required, in addition to antigen recognition, for T cell activation. Normally, in the absence of CD28 signaling T cells are inactive. Dumitriu and collegues hypothesized that these T cells might use alternative costimulatory receptors—and indeed, they identified two such receptors that were expressed in this cell type and could drive an inflammatory phenotype. Additionally, they found that ligands for these receptors were present in plaques and were expressed on circulating monocytes. By inhibiting the costimulatory receptors in vitro, the researchers reversed the damaging effects of the CD4+CD28null T cells.

The work of Dumitriu et al. suggests that blocking the alternative costimulatory receptors might be a promising strategy for stabilizing patients with ACS. Although this work is an important advance, the mechanisms of immune regulation in plaque rupture are complex, and additional studies are needed to understand CD4+CD28null T cell function to safely and effectively target the pathway in human patients.

I. E. Dumitriu et al., High levels of costimulatory receptors OX40 and 4-1BB characterize CD4+CD28null T cells in patients with acute coronary syndrome. Circ. Res. 110, 857–869 (2012). [Abstract]

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