Published Online
on April 19, 2004

A more recent version of this article appeared on April 27, 2004

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Submitted on August 22, 2003
Revised on January 9, 2004
Accepted on January 15, 2004

B7-1/B7-2 Costimulation Regulates Plaque Antigen-Specific T-Cell Responses and Atherogenesis in Low-Density Lipoprotein Receptor-Deficient Mice

Chiara Buono MD, Hong Pang MD, Yasushi Uchida MD, PhD, Peter Libby MD, Arlene H. Sharpe MD, PhD, and Andrew H. Lichtman MD, PhD^*

From the Immunology Research Division and the Vascular Research Division, Department of Pathology (C.B., H.P., Y.U., A.H.S., A.H.L.), and Cardiovascular Division, Department of Medicine (P.L.), Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass.

^* To whom correspondence should be addressed. E-mail: alichtman{at}rics.bwh.harvard.edu.

Background--Several lines of evidence indicate that T-cell responses influence the progression of atherosclerotic disease. Interferon- (IFN-)-producing T cells specific for lesional antigens, including oxidized LDLs and heat shock protein 60 (HSP60), may promote lesion development as well as plaque instability. B7-1 and B7-2 are closely related molecules expressed on antigen-presenting cells that provide costimulatory signals for T-cell activation. This study tested the hypothesis that the ability of T cells to influence atherosclerosis depends on B7-1/B7-2 costimulation.

Methods and Results--B7-1/B7-2/LDL receptor (LDLR)-deficient mice and LDLR-deficient control mice were fed a 1.25% cholesterol or control diet for 8 and 20 weeks. Total serum cholesterol levels and extent and phenotype of atherosclerosis were analyzed. Splenic and lymph node CD4⁺ T cells from the animals were cultured with mouse recombinant HSP60 or media and antigen-presenting cells and analyzed for IFN- and interleukin-4 production. The absence of B7-1 and B7-2 significantly reduced early cholesterol diet-induced atherosclerotic lesion development in LDLR-deficient mice compared with B7-1/B7-2-expressing control mice. Furthermore, CD4⁺ T cells from the cholesterol-fed B7-deficient mice secreted a significantly lower amount of IFN- in response to mouse HSP60 in vitro than did T cells from B7-expressing control mice.

Conclusions--The data show that B7-1 and B7-2 regulated the development of atherosclerotic lesions and the priming of lesional antigen-specific T cells. This study highlights the B7-CD28 pathway as a potentially important target for immunomodulation of atherosclerosis.

Key words: atherosclerosis • immune system • cytokines • heat-shock proteins • T-lymphocytes

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