B7-1/B7-2 costimulation regulates plaque antigen-specific T-cell responses and atherogenesis in low-density lipoprotein receptor-deficient mice

Circulation. 2004 Apr 27;109(16):2009-15. doi: 10.1161/01.CIR.0000127121.16815.F1. Epub 2004 Apr 19.

Abstract

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.

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-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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antigens / immunology
  • Antigens, CD / metabolism*
  • Arteriosclerosis / immunology*
  • Arteriosclerosis / pathology
  • B7-1 Antigen / metabolism*
  • B7-2 Antigen
  • CD4-Positive T-Lymphocytes / immunology*
  • Chaperonin 60 / immunology
  • Cholesterol / blood
  • Cytokines / biosynthesis
  • Lymphocyte Activation
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Knockout
  • Receptors, LDL / genetics

Substances

  • Antigens
  • Antigens, CD
  • B7-1 Antigen
  • B7-2 Antigen
  • Cd86 protein, mouse
  • Chaperonin 60
  • Cytokines
  • Membrane Glycoproteins
  • Receptors, LDL
  • Cholesterol