Atherosclerotic plaque T cells produce cytokines but do not exhibit signs of T-cell receptor-mediated activation

Abstract

Abstract T-cell activation in the atherosclerotic plaque has been proposed to be a key event promoting lesion inflammation and destabilization. Although T cells and antigen-presenting cells are present in the plaque, it is unclear whether primary activation or secondary re-activation of T cells occurs in the lesion. We sought to quantify and characterize activated plaque T-cells in experimental atherosclerosis utilizing transgenic reporter mice of TCR-signalling (Nur77-GFP) or cytokine production (IFN-γ-YFP). As has been previously described, splenic Nur77hi T cells displayed markers consistent with a recently activated phenotype (PD-1+CD44+). Importantly, we observed very low levels of Nur77hi CD4+ or CD8+ T cells in the atherosclerotic aorta of Nur77-GFP-Apoe−/− mice compared to other tissues. In line with these findings, adoptive transfer of splenic Nur77-GFP CD4+ T cells to lymphodeficient atherosclerotic Rag1−/−Apoe−/− mice revealed markedly lower levels of Nur77hi T cells in plaque compared to lymphoid organs 10 weeks post-transfer, suggesting limited TCR-mediated activation in plaques. Conversely, analysis of atherosclerotic plaques from Apoe−/−IFN-γ-YFP reporter mice demonstrated robust IFN-γ production by CD4+ and CD8+ T cells. Altogether these results indicate that levels of cytokine release are above that of TCR-mediated T-cell activation, suggesting that antigen-driven activation of T cells in the plaque is not key for mediating T-cell driven atherosclerosis.