A functional role for inducible costimulator (ICOS) in atherosclerosis.
BACKGROUND
Lymphocytes appear to influence atherosclerosis by altering cytokine production. Whereas primary lymphocyte activation requires T cell receptor ligation, costimulatory signals also appear requisite for generation of a functional T cell response. Inducible costimulator (ICOS) is a newly discovered T cell molecule with a dual role in immune mediated disorders. Herein, we tested the importance of ICOS in atherosclerosis.


RESULTS
Atherosclerotic plaques from ApoE-KO mice were studied immunohistochemically for the presence and localization of ICOS and its receptors and its expression in splenocytes. ApoE-KO mice were immunized with human ICOS/Fc-chimera or non-fused Fc and either provided a chow diet for 6 weeks, or a high fat diet for 8 weeks. ICOS and its ligand were abundantly expressed within plaques from ApoE-KO mice: Spleen cells from atherosclerotic mice exhibited lowered constitutive expression of ICOS yet priming with oxLDL enhanced ICOS expression dose-dependently. In mice induced to develop fatty streaks and to generate ICOS blocking antibodies, early atherosclerosis was increased by approximately 77% whereas upon inducing more advanced lesions, the increase in plaque area upon ICOS blockade group was approximately 36%. IFN-gamma secretion by oxLDL-primed splenocytes in ICOS-immunized mice increased whereas IL-10 secretion diminished as compared to control animals. A similar trend in cytokine production was evident in the lesion by immunohistochemistry.


CONCLUSIONS
ICOS appears as an influential costimulatory pathway in atherosclerosis that may play a protective rather that a proatherogenic role.
Afek
Arnon
A
Department of Cardiology and the Cardiovascular Research Laboratory, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, 6 Weizmann St., Tel-Aviv, Israel.
Harats
Dror
D
Roth
Arie
A
Keren
Gad
G
George
Jacob
J
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D001011:Aorta / Q000737:chemistry / Q000473:pathology; D001018:Aortic Diseases / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology; D004036:Diet, Atherogenic; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000150:complications; D007114:Immunization; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000276:immunology; D060889:Inducible T-Cell Co-Stimulator Protein; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D007518:Isoantibodies / Q000096:biosynthesis / Q000276:immunology; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011993:Recombinant Fusion Proteins / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
D000945:Antigens, Differentiation, T-Lymphocyte; D001057:Apolipoproteins E; D001323:Autoantibodies; C556692:ICOS protein, human; C556694:Icos protein, mouse; D007141:Immunoglobulin Fc Fragments; D060889:Inducible T-Cell Co-Stimulator Protein; D007518:Isoantibodies; D008077:Lipoproteins, LDL; D011993:Recombinant Fusion Proteins; C099252:oxidized low density lipoprotein; D016753:Interleukin-10; D007371:Interferon-gamma