T-cells from advanced atherosclerotic lesions recognize hHSP60 and have a restricted T-cell receptor repertoire

Abstract

Atherosclerosis is a multifactorial, chronic-inflammatory disease for which the underlying cause remains unknown. It is also well documented that T-cells are among the first cells to migrate into the arterial intimal vessel layer, but their function there is still unexplained. Clinical and experimental data have provided evidence that atherosclerosis starts as an autoimmune reaction based on humoral and cellular immunity against a phylogenetically highly conserved stress protein, heat shock protein 60 (HSP60). In the present study, we phenotypically characterized T-cells from endarterectomized specimens of the carotid artery, and tested their reactivity to human HSP60. In addition, the T-cell receptor repertoire of the T-cell lines was defined by immunoscope analysis. We found a mixed population of CD4(+) and CD8(+) intralesional T-cells, with a slight predominance of CD8(+) cells. IFN-gamma production prevailed over IL-4 production. The T-cell reaction against human HSP60 was significantly increased in intralesional cells compared to peripheral T-cells. The lesion-derived T-cells showed an oligoclonally-restricted repertoire, in contrast to the polyclonal pattern of PBMC. These results clearly show that HSP60 is a major antigenic candidate, and that an oligoclonal T-cell expansion takes place in advanced human atherosclerotic lesions.

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).…”

Tolerization against atherosclerosis using heat shock protein 60

“…Genetically normocholesterolemic rabbits immunized with mbHSP65 (in the present context, mbHSP65 is always used as a paradigmatic and potent representative of bacterial HSP60) develop atherosclerotic plaques irrespective of their diet with low or high-cholesterol levels, and T cells isolated from these lesions specifically respond to mbHSP65 in vitro (Xu et al , 1993aMetzler et al 1999), a finding similar to that in humans (Rossmann et al 2008;Benagiano et al 2005). Both C57BL/6J mice, fed high-cholesterol diet, and LDLr −/− mice, fed a normal chow diet, revealed enhanced early atherosclerotic lesions after immunization with mbHSP65 (Afek et al 2000;George et al 1999).…”

“…These DCs can function as antigen-presenting cells (APCs) and thereby capture potentially harmful exogenous or autoantigens and present these to T cells and macrophages. Lesion-derived T cells display an oligoclonally restricted repertoire in contrast to the polyclonal pattern of peripheral blood mononuclear cells (PBMCs), indicating that oligoclonal T cell expansion can take place in human atherosclerotic lesions (Rossmann et al 2008). We have recently shown that these early autoreactive intralesional T cells, derived from early, clinically still inapparent human atherosclerotic lesions, can specifically react to certain hHPS60 epitopes (Almanzar et al 2012).…”

In vivo imaging of the effect of LPS on arterial endothelial cells: molecular imaging of heat shock protein 60 expression

“…As a matter of fact, this goal has already been achieved for arthritogenic and arthritoprotective HSP60 T-cell epitopes (Prakken et al 1997;van Eden and Waksman 2003), while for atherosclerosis, this is only true for B-cell epitopes (Perschinka et al 2003(Perschinka et al , 2007. However, similar to the situation in synovial tissues of animals and humans, accumulation of HSP60-reactive T cells in atherosclerotic plaques compared to peripheral blood was found in humans (Benagiano et al 2003(Benagiano et al , 2005 and rabbits (Rossmann et al 2008;Xu et al 1993a). In mice, the disease could be transferred by HSP60-specific T cells to syngeneic recipients (George et al 2001).…”