Impaired regulatory T-cell response and enhanced atherosclerosis in the absence of inducible costimulatory molecule

Background - T-cell-mediated immunity contributes to the pathogenesis of atherosclerosis, but little is known about how these responses are regulated. We explored the influence of the inducible costimulatory molecule ( ICOS) on atherosclerosis and associated immune responses. Methods and Results - Bone morrow chimeras were generated by transplanting ICOS-deficient or wild-type bone marrow into irradiated atherosclerosis-prone, LDR receptor-deficient mice, and the chimeric mice were fed a high-cholesterol diet for 8 weeks. Compared with controls, mice transplanted with ICOS-deficient marrow had a 43% increase in the atherosclerotic burden, and importantly, their lesions had a 3-fold increase in CD4(+) T cells, as well as increased macrophage, smooth muscle cell, and collagen content. CD4(+) T cells from ICOS-deficient chimeras proliferated more and secreted more interferon-gamma and tumor necrosis factor-alpha than T cells from control mice, which suggests a lack of regulation. FoxP3(+) regulatory T cells (Treg) were found to constitutively express high ICOS levels, which suggests a role for ICOS in Treg function. ICOS- deficient mice had decreased numbers of FoxP3(+) Treg and impaired in vitro Treg suppressive function compared with control mice. Conclusions - ICOS has a key role in regulation of atherosclerosis, through its effect on regulatory T-cell responses.