Oligoclonal T cell expansions in atherosclerotic lesions of apolipoprotein E-deficient mice

Abstract

T cells are present in atherosclerotic lesions at all stages of development. They exhibit activation markers and are particularly prominent at sites of plaque rupture. This suggests that T-cell-mediated immune responses are involved in the pathogenesis of atherosclerosis. Antigen- specific T cells reactive with oxidized lipoproteins and heat shock proteins have been isolated from plaques, indicating that local activation and clonal expansion might occur. To analyze different stages of atherosclerosis, we have used a murine model. Targeted deletion of the apolipoprotein E gene results in severe hypercholesterolemia and spontaneous atherosclerosis, with lesions containing large numbers of T cells and macrophages. We have analyzed mRNA for T-cell antigen receptors (TCRs) from aortic fatty streaks, early fibrofatty plaques, and advanced fibrofatty plaques of such mice. Polymerase chain reaction amplification of complementarity-determining region 3 (CDR3 region) of TCRs was followed by spectratyping of fragment lengths. This analysis detected all types of variable (V) segments with a gaussian distribution of CDR3 in lymph nodes. In contrast, a restricted heterogeneity was found in atherosclerotic lesions, with expansion of a limited set of Vβ and Vα segments and a monotypic or oligotypic CDR3 spectrum in each lesion. Vβ6 was expressed in all lesions; Vβ5.2, Vβ16, Vα34s, and Vα9, in the majority of lesions; and Vβ6, Vβ5.2, and Vα34S, in lesions at all 3 stages of development. The strongly skewed pattern of the CDR3 region in the TCR is indicative of oligoclonal expansions of T cells and suggests the occurrence of antigen-driven T-cell proliferation in atherosclerosis.