T lymphocyte autoreactivity in inflammatory mechanisms regulating atherosclerosis

Abstract

Atherosclerosis has been clearly demonstrated to be a chronic inflammatory disease of the arterial wall. Both cells of the innate and the acquired immune system, particularly monocytes and T lymphocytes, are implicated in the atherogenic process, producing different cytokines with pro- and anti-inflammatory effects. The majority of pathogenic T cells involved in atherosclerosis are of the Th1 profile, that has been correlated positively with coronary artery disease. Many studies conducted to evaluate the molecular factors responsible for the activation of T cells have demonstrated that the main antigenic targets in atherosclerosis are modified endogenous structures. These self-molecules activate autoimmune reactions mainly characterized by the production of Th1 cytokines, thus sustaining the inflammatory mechanisms involved in endothelial dysfunction and plaque development. In this paper we will summarize the different T-cell subsets involved in atherosclerosis and the best characterized autoantigens involved in cardiovascular inflammation.

Figure 1

Schematic representation of T lymphocyte subset activation within atherosclerotic plaque. Different self-structures are expressed in the intima of the vessel wall and subjected to enzymatic/oxidative modifications. These modified molecules are taken up by dendritic cells and presented to CD4+ T helper cells via MHC class II molecules. Antigen presentation promotes T lymphocyte activation and secretion of different cytokines. Effector CD4+ Th1 cells produce pro-inflammatory cytokines, particularly IFN-γ, with proatherogenic effects. Activated Th2 lymphocytes secrete IL-4 and IL-5 which promote the differentiation of B cells in plasma cells and the production of specific antibodies. Some infiltrated T cells upon activation differentiate in Th17 lymphocytes characterized by the production of IL-17, but their role remains controversial. Regulatory T cells (Tregs) downregulate inflammation by secretion of TGF-β and IL-10. The pro-inflammatory mediators released by activated T cells reduce the stability of the lesion promoting plaque rupture and thrombotic events.