The role of T and B cells in human atherosclerosis and atherothrombosis

Abstract

Far from being merely a passive cholesterol accumulation within the arterial wall, the development of atherosclerosis is currently known to imply both inflammation and immune effector mechanisms. Adaptive immunity has been implicated in the process of disease initiation and progression interwined with traditional cardiovascular risk factors. Although the body of knowledge regarding the correlation between atherosclerosis and immunity in humans is growing rapidly, a relevant proportion of it derives from studies carried out in animal models of cardiovascular disease (CVD). However, while the mouse is a well-suited model, the results obtained therein are not fully transferrable to the human setting due to intrinsic genomic and environmental differences. In the present review, we will discuss mainly human findings, obtained either by examination of post-mortem and surgical atherosclerotic material or through the analysis of the immunological profile of peripheral blood cells. In particular, we will discuss the findings supporting a pro-atherogenic role of T cell subsets, such as effector memory T cells or the potential protective function of regulatory T cells. Recent studies suggest that traditional T cell-driven B2 cell responses appear to be atherogenic, while innate B1 cells appear to exert a protective action through the secretion of naturally occurring antibodies. The insights into the immune pathogenesis of atherosclerosis can provide new targets in the quest for novel therapeutic targets to abate CVD morbidity and mortality.

Keywords: B cells; T cells; atherosclerosis; coronary artery disease; effector memory T cells.

Figure 1

T cells and atherosclerotic plaque development. Within secondary and tertiary lymphoid organs, activated dendritic cells polarize naive CD4⁺ T helper (Th) cells in different types of effector T cell through antigen presentation alongside secretion of cytokines and co-stimulation. Th1, Th2 and Th17 subsets are categorized by the cytokine they release. Tolerogenic dendritic cells prime naive CD4⁺ cells toward a regulatory phenotype (regulatory T cells: T_regs). The ontogeny of CD28^nullCD4⁺ is currently a matter of active investigation. Upon acquisition of an effector memory phenotype, characterized by the expression of CD45RO, human leucocyte antigen D-related (HLA-DR) and chemokines receptor CCR5, activated T cells recirculate in peripheral blood. The secretion of cytokines and chemokines from the plaque drives their homing to the atherosclerotic lesion, where they exert diverse actions. Th1 cells promote endothelial disfunction, lipid accumulation in macrophages with subsequent foam cell formation, and cell death through the secretion of their master cytokine interferon (IFN)-γ, exerting a pro-atherogenic effect. The role of Th2 has not yet been elucidated, but appears to be atheroprotective, due possibly to inhibition of Th1 cells. The role of Th17 is currently under intense investigation. T_regs appear to be atheroprotective through the induction of tolerance, the inhibition of atherogenic T cell subsets and suppression of inflammation. CD28^nullCD4⁺ exert a pro-atherogenic action through the secretion of proinflammatory cytokines and cell-mediated cytotoxicity. They were shown to resist T_reg inhibition. Human atherosclerotic plaques are also infiltated with CD8⁺ cytotoxic T cells, which exert an atherogenic effect through induction of cell death. SMC = smooth muscle cells; IL-4: interleukin 4; IL17: interleukin 17; FoxP3: forkhead box protein 3; OX40: CD 131.

Figure 2

Role of B cells and Immunoglobulins in atherosclerotic lesion development. Under chronic inflammatory conditions, B2 cells become activated by T follicular helper cells within lymphoid-like structures in the vessel wall. They undergo maturation into antibody secreting cells within the plaque where they directly secrete immunoglobulins. Further immunoglobulins, including B1 cell-secreted naturally occurring antibodies, are secreted in other districts and reach the plaque through the systemic circulation. The presence of B1 cells within the plaque is currently a matter of debate. Immunoglobulins show a wide range of specificities, including oxidized low-density lipoproteins (oxLDL) and heat shock protein 60 (HSP60). Naturally occurring immunoglobulin (Ig)M appears to exert a protective action by inhibiting the uptake of oxLDL by macrophages and by favouring the clearance of apoptotic bodies, which is aided by local deposition of complement. Conversely, IgG directed against oxLDL may enhance the uptake of cholesterol, thus favouring atherosclerosis. A protective effect, however, was shown for IgG specific for peptide 210 of ApoB100. IgG cross-reacting with bacterial antigens were shown to be produced within lesione, suggesting a role for infectious agents. IgG recognizing endothelial antigens, e.g. HSP60, may directly cause endothelial disfunction. SMC = smooth muscle cells.