B7-1/B7-2 costimulation regulates plaque antigen-specific T-cell responses and atherogenesis in low-density lipoprotein receptor-deficient mice.
BACKGROUND
Several lines of evidence indicate that T-cell responses influence the progression of atherosclerotic disease. Interferon-gamma (IFN-gamma)-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.


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-gamma 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-gamma 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.
Buono
Chiara
C
Immunology Research Division and the Vascular Research Division, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass 02115, USA.
Pang
Hong
H
Uchida
Yasushi
Y
Libby
Peter
P
Sharpe
Arlene H
AH
Lichtman
Andrew H
AH
D000818:Animals; D000941:Antigens / Q000276:immunology; D015703:Antigens, CD / Q000378:metabolism*; D001161:Arteriosclerosis / Q000276:immunology* / Q000473:pathology; D018122:B7-1 Antigen / Q000378:metabolism*; D051940:B7-2 Antigen; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018834:Chaperonin 60 / Q000276:immunology; D002784:Cholesterol / Q000097:blood; D016207:Cytokines / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000235:genetics
D000941:Antigens; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D018834:Chaperonin 60; D016207:Cytokines; D008562:Membrane Glycoproteins; D011973:Receptors, LDL; D002784:Cholesterol