In humans, atherosclerotic plaques contain blood-borne inflammatory and immune cells (~40% of cells present within the plaques express macrophage markers, ~10% are CD3+ T cells) as well as endothelial cells, smooth muscle cells, extracellular matrix proteins, lipids and acellular lipid-rich debris. Small populations of mast cells, B cells and dendritic cells (DCs) are also present in plaques and, together with T cells, monocytes and macrophages, might traffic between the blood, the atherosclerotic lesion and the regional lymph nodes. Many of these immune cells show signs of activation and produce proinflammatory cytokines, including interferon-γ (IFNγ) and tumour-necrosis factor (TNF). Inflammation is induced by innate immunity and adaptive immunity. The two arms of the immune response can either promote or attenuate atherosclerosis.

Recent studies suggest that subtypes of T cells, called regulatory T cells, previously shown to maintain immunologic tolerance to self and nonself antigens, are powerful inhibitors of atherosclerosis (Ait-Oufella et al, Nature Medecine, 2006).

Mediators in atherogenesis

Pathogenic and regulatory immunity in atherosclerosis Candidate antigens [oxidized lipoproteins (oxLDL), heat shock proteins (HSP), phosphorylcholine (PC), apoptotic bodies. . . ] from the plaque are taken up by Antigen Presenting Cells (APC) and may induce Tcell responses. Maturation of APC is necessary for T-cell priming.

Costimulation signals mediated by CD40/CD40L pathway as well as cytokine production are critical for Th1 and Th2 responses. Both IFN-γ (Th1) and IL-4 (Th2) have been shown to promote atherogenesis. Production of IL-5 by Th2 cells is important for protective antibody production by B lymphocytes in response to immunization with oxLDL.

Distinct subsets of APCs, called “tolerogenic” cells, induce the differentiation of the regulatory T-cell subset (Treg). The development of CD4+CD25+Foxp3+ Treg cells occurs in the thymus and requires TCR and CD28 engagement among other yet unknown factors.

Interestingly, production of IL-2 by pathogenic Th1 cells is essential for the survival and maintenance of this Treg subset in the periphery. Other Treg cells of the Tr1 type may not express Foxp3 and are mainly induced in the periphery in response to antigen stimulation. Both types of Treg cells use IL-10 and/or TGF-b to suppress the proliferation of pathogenic T cells in vivo. IL-6, produced by macrophages in response to TLR stimulation, may contribute to the inhibition of Treg function.

Lymphoid organs are specialized in antigen presentation and may be the major site of pathogenic or tolerogenic antigen presentation and T-cell priming in atherosclerosis. Antigen presentation may also occur within the atherosclerotic plaque, which is rich in cells with antigen-presenting capacity (macrophages and dendritic cells).

Continuous trafficking of immune cells between the inflammed atherosclerotic artery and the lymphoid organs may be necessary to mount an adaptive immune response. CD28 engagement and IL-2 production by pathogenic T cells are required for Treg cell survival and maintenance in the periphery. Treg cells suppress the pathogenic response through IL-10, TGF-b, and/or cell-cell contact-dependent mechanisms.

The precise mechanisms that drive a pathogenic or a regulatory immune response in atherosclerosis are currently unknown.