The Role of the T‐cell Inducible Co‐stimulatory Molecule ICOS in the Development of Atherosclerosis

Abstract

Background T-cell-mediated immune responses to plaque antigens are important in mediating the inflammatory response in atherosclerosis. The inducible co-stimulatory molecule (ICOS) is expressed on activated T cells after antigen stimulation and has important T-cell regulatory functions. Method Bone morrow chimeras were produced by transplanting ICOS-deficient bone marrow into atherosclerosis-prone low-density lipoprotein receptor (LDLR)-deficient mice. Atherosclerosis was analyzed after 8 weeks of high-fat diet. Results ICOS deficiency significantly increased atherosclerosis. Mice transplanted with ICOS deficient cells had an increase in fractional lesion area in the aortic sinuses from 37.4 ± 2.2% to 53.6 ± 2.2% (P<0.0001), a 43% increase in the atherosclerotic burden. Immunohistochemistry of the atherosclerotic lesions demonstrated a 3 to 4 fold increase in CD4(+) T cell infiltration, as well as increased macrophage infiltration. This increase correlated with a significant increase in the in-vitro proliferation of spleen CD4(+) T cell stimulated with anti-CD3 antibodies. Moreover, there was also an increase in the specific proliferation towards Oxidized-LDL (10 mg/ml) in mice transplanted with ICOS deficient cells. This corresponded with an increased pro-inflammatory (IL-2, IFN-γ, TNFα) cytokine profile in these cells by both protein level secretion and RT-PCR analysis and a decrease in the expression of the anti-inflammatory cytokine TGF-β. Serum levels of the pro-inflammatory chemokine MCP-1 was increased in these mice. Conclusion ICOS has a role in the development of atherosclerosis by down regulating the pro-inflammatory immune response.