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(Circulation. 2006;114:2047-2055.)
© 2006 American Heart Association, Inc.

Molecular Cardiology

Impaired Regulatory T-Cell Response and Enhanced Atherosclerosis in the Absence of Inducible Costimulatory Molecule

Israel Gotsman, MD; Nir Grabie, PhD; Rajat Gupta, BS; Rosa Dacosta, AB; Malcolm MacConmara, MB, BCh; James Lederer, PhD; Galina Sukhova, PhD; Joseph L. Witztum, MD; Arlene H. Sharpe, MD, PhD; Andrew H. Lichtman, MD, PhD

From the Immunology and Vascular Research Divisions (I.G., N.G., R.G., R.D., A.H.S., A.H.L.), Department of Pathology, Donald W. Reynolds Cardiovascular Clinical Research Center (G.S.), Department of Medicine, and Department of Surgery (M.M., J.L.), Brigham and Women’s Hospital, and Harvard Medical School, Boston, Mass; and Department of Medicine (J.L.W.), University of California, San Diego, La Jolla, Calif.

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

Received April 10, 2006; revision received August 2, 2006; accepted September 8, 2006.

Background— T-cell–mediated immunity contributes to the pathogenesis of atherosclerosis, but little is known about how these responses are regulated. We explored the influence of the inducible costimulatory molecule (ICOS) on atherosclerosis and associated immune responses.

Methods and Results— Bone morrow chimeras were generated by transplanting ICOS-deficient or wild-type bone marrow into irradiated atherosclerosis-prone, LDR receptor–deficient mice, and the chimeric mice were fed a high-cholesterol diet for 8 weeks. Compared with controls, mice transplanted with ICOS-deficient marrow had a 43% increase in the atherosclerotic burden, and importantly, their lesions had a 3-fold increase in CD4⁺ T cells, as well as increased macrophage, smooth muscle cell, and collagen content. CD4⁺ T cells from ICOS-deficient chimeras proliferated more and secreted more interferon- and tumor necrosis factor- than T cells from control mice, which suggests a lack of regulation. FoxP3⁺ regulatory T cells (Treg) were found to constitutively express high ICOS levels, which suggests a role for ICOS in Treg function. ICOS-deficient mice had decreased numbers of FoxP3⁺ Treg and impaired in vitro Treg suppressive function compared with control mice.

Conclusions— ICOS has a key role in regulation of atherosclerosis, through its effect on regulatory T-cell responses.

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