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(Circulation Research. 2008;103:1220.)
© 2008 American Heart Association, Inc.

Reviews

T-Cell Costimulation and Coinhibition in Atherosclerosis

Israel Gotsman, Arlene H. Sharpe, Andrew H. Lichtman

From the Heart Institute (I.G.), Hadassah University Hospital, Jerusalem; and Department of Pathology (A.H.S., A.H.L.); and Immunology and Vascular Research Divisions (A.H.L.), Department of Pathology, Harvard Medical School and Brigham and Women’s Hospital, Boston, Mass.

Correspondence to Andrew H. Lichtman, MD PhD, Department of Pathology, Brigham and Women’s Hospital, 77 Ave Louis Pasteur, NRB 752N, Boston, MA 02115. E-mail alichtman{at}rics.bwh.harvard.edu

Evidence from many human and rodent studies has established that T lymphocytes enhance inflammation in atherosclerotic plaques and contribute to lesion progression and remodeling. Recent work also indicates that regulatory T cells are important in limiting proatherogenic T-cell responses. Given the important role of T cells in atherosclerosis, there is a need to fully understand how proatherogenic T cells are activated and regulated. Antigen-dependent activation of naïve T cells, leading to clonal expansion and effector T-cell differentiation, and effector and memory T cells, is enhanced by signals provided by costimulatory molecules expressed by antigen presenting cells, which bind to receptors on the T cells. In addition, T-cell responses to antigen are negatively regulated by coinhibitory molecules expressed by antigen-presenting cells, which bind to receptors on T cells. Two major families of costimulatory molecules include the B7 and the tumor necrosis factor (TNF) families. These molecules bind to receptors on T cells belonging to the CD28 or TNF receptor families, respectively. The best-defined coinhibitors and their receptors belong to the B7 and CD28 families. Recent work has begun to define how these T-cell costimulatory and coinhibitory pathways influence atherosclerosis, largely in mouse models of the disease. Profound effects are attributable to molecules in both the B7/CD28 (B7-1/2, ICOS, and PDL-1/2) and the TNF/TNF receptor (CD40, OX40, and CD137) families. One emerging theme is that both pathogenic effector T-cell responses and regulatory T cells are influenced by overlapping sets of costimulators and coinhibitors. These complexities must be considered as immunotherapeutic approaches for atherosclerotic disease are developed.

Key Words: atherosclerosis • costimulation • coinhibition • T lymphocytes