Oligoclonal T Cell Expansions in Atherosclerotic Lesions of Apolipoprotein E–Deficient Mice

Abstract

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 complementaritydetermining 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 V␤ and V␣ segments and a monotypic or oligotypic CDR3 spectrum in each lesion. V␤6 was expressed in all lesions; V␤5.2, V␤16, V␣34s, and V␣9, in the majority of lesions; and V␤6, V␤5.

Characterization of Resident B Cells of Vascular Walls in Human Atherosclerotic Patients

“…The question of clonality of resident T cells in atherosclerotic lesions has also been addressed, with contrasting results. Initial data pointed to a polyclonal origin for T cells in plaques (45,46), but more recent studies demonstrated that resident T cells were locally activated by OxLDL and heat shock protein, using a restricted TCR repertoire (47,48).…”

Invariant natural killer T cells: Linking inflammation and neovascularization in human atherosclerosis

“…In pioneering studies on ApoE-deficient mice under high cholesterol diet, the presence of iNKT cells was suggested by RT-PCR [13,14,32]. However, to date, iNKT cells have neither been isolated from plaques nor functionally characterized.…”

In Vivo Administration of the Recombinant IL-7/Hepatocyte Growth Factor β Hybrid Cytokine Efficiently Restores Thymopoiesis and Naive T Cell Generation in Lethally Irradiated Mice after Syngeneic Bone Marrow Transplantation

“…TCR Vb CDR3 spectratype analysis CDR3 spectratype analysis of TCR b-chain was performed as described (31). Briefly, RNA was extracted from purified donor-origin splenic CD3 + T cells of BMT mice.…”

“…cDNA was synthesized by using oligo(dT) primer and SuperScript II reverse transcriptase (Invitrogen). PCR was performed with a forward primer specific for one of the 14 TCR Vb families along with a constant Cb reverse primer labeled with fluorescent FAM, as previous described (31). The size distribution of each fluorescent PCR product was analyzed on a genetic analyzer (ABI3730; Applied Biosystems) using GeneMarker software.…”