Abstract
Clinical complications of atherosclerosis are almost exclusively linked to destabilization of the atherosclerotic plaque. Batf3-dependent dendritic cells specialize in cross-presentation of necrotic tissue-derived epitopes to directly activate cytolytic CD8 Tcells. The mature plaque (necrotic, containing dendritic cells and CD8 Tcells) could offer the ideal environment for cross-presentation, resulting in cytotoxic immunity and plaque destabilization. Ldlr−/− mice were transplanted with batf3−/− or wt bone marrow and put on a western type diet. Hematopoietic batf3 deficiency sharply decreased CD8α+ DC numbers in spleen and lymph nodes (>80%; P < 0,001). Concordantly, batf3−/− chimeras had a 75% reduction in OT-I cross-priming capacity in vivo. Batf3−/− chimeric mice did not show lower Tcell or other leukocyte subset numbers. Despite dampened cross-presentation capacity, batf3−/− chimeras had equal atherosclerosis burden in aortic arch and root. Likewise, batf3−/− chimeras and wt mice revealed no differences in parameters of plaque stability: plaque Tcell infiltration, cell death, collagen composition, and macrophage and vascular smooth muscle cell content were unchanged. These results show that CD8α+ DC loss in hyperlipidemic mice profoundly reduces cross-priming ability, nevertheless it does not influence lesion development. Taken together, we clearly demonstrate that CD8α+ DC-mediated cross-presentation does not significantly contribute to atherosclerotic plaque formation and stability.
Highlights
On an MHCI molecule followed by a potent CD8+ Tcell activation[5]
We opted for cross-presentation as plausible candidate, considering that all components for effective cross-presentation are present in the advanced atherosclerotic plaque and that several genes involved in cross-presentation were more expressed in ruptured compared to early atherosclerotic lesions of CVD patients
Exposure to high LDL/VLDL levels in advanced atherosclerosis would most likely not interfere with the cross-presentation machinery, as we showed that systemic cross-presentation efficacy in mice was not affected by hyperlipidemia
Summary
Mouse dendritic cells (CD8α + or CD103+ DCs) appear to be highly efficient cross-presenting cells[6], uniquely qualified to cross-present dead cell-associated antigens[7]. A recent study has demonstrated that cytotoxic CD8+ Tcells promote development of a vulnerable atherosclerotic plaque in mice, implicating cytolytic Tcell immunity in plaque destabilization[22] Combining these arguments led to the following intriguing hypothesis: Cross-presentation, by mounting a cytolytic CD8+ Tcell immune response against cap/plaque material, might be crucial in the destabilization of the advanced plaque which generally precedes plaque rupture, thrombi formation and infarcts. Possible protection by cross-presenting DCs was observed in the flt3−/− ldlr−/− mouse, where depletion of Flt3L-dependent DCs resulted in aggrevated atherosclerosis[26] Each of these studies implies severe modifications of the entire immune system, which greatly impedes assessment of purely cross-presentation related effects. The severe defect in cross-presentation in batf3−/− chimeras did not translate into apparent differences in CD8+ Tcell numbers, nor did it significantly affect atherosclerotic plaque size or composition
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