Immunity and Inflammation in Atherosclerosis

Abstract

There is now overwhelming experimental and clinical evidence that atherosclerosis is a chronic inflammatory disease. Lessons from genome-wide association studies, advanced in vivo imaging techniques, transgenic lineage tracing mice, and clinical interventional studies have shown that both innate and adaptive immune mechanisms can accelerate or curb atherosclerosis. Here, we summarize and discuss the pathogenesis of atherosclerosis with a focus on adaptive immunity. We discuss some limitations of animal models and the need for models that are tailored to better translate to human atherosclerosis and ultimately progress in prevention and treatment.

Keywords: adaptive immunity; atherosclerosis; immunity; inflammation; myeloid cells; vaccination.

Figure 1:. Activation of T cells is a hallmark of atherosclerosis.

(a) During feeding with a Western Diet (WD), CD4⁺ T-helper cells from atherosclerosis-prone Apoe^−/− build-up a significant immune memory with more than one half of T cells express markers of CD62L⁻ CD44⁺ T-effector memory cells (T_EM) and CD62L⁺ CD44⁺ central-memory cells (T_CM) when compared to atherosclerosis-free wildtype (WT) mice. (b) Along with enhanced T cell activation, lymph nodes draining the aorta and supra-aortic arteries (cervical, axillary lymph nodes) massively increase in size. Courtesy of D. Wolf and K. Ley

Figure 2:. T cell polarization in atherosclerosis.

Naïve T helper cells (T_H) acquire the complete phenotype of an effector T cell in the plaque after presentation of antigenic peptides from ApoB by antigen-presenting cells (APCs). Therefore, an APC takes up (oxidized) LDL-cholesterol particles, processes, and presents peptides from ApoB on MHC-II. The T cell recognized this complex by a specific T cell receptor (TCR). This process is guided by the binding of co-stimulatory ligands to their corresponding receptors on T cells. As a result of co-stimulatory signals and cytokines secreted by the APC, T cells express transcription factors (denoted in the cells) that favor the differentiation into distinct T_H-types. These express specific cytokines that can either act in an atheroprotection or pro-atherogenic manner. The relevance for atherosclerosis remains controversial for some T_H-phenotypes.

Figure 3:. Decline of protective T-regulatory cells (T_reg) in the course of atherosclerosis.

(a) As disease progresses, the pool of T_reg-dominated antigen-specific T cells is overwhelmed by effector T cells (T_eff) with a presumably pro-atherogenic function. (b) Over time, T_regs expressing their defining transcription factor FoxP3 start to express alternative T_H-transcription factors, such as RORγ-T (T_H17), Bcl-6 (T_FH), or T-bet (T_H1). FoxP3 either remains co-expressed or disappears. Likely, this switch into FoxP3-low expressed or -negative exT_regs may be caused by antigen-specificity of the T cell, the cytokine milieu in the atherosclerotic plaque, or the loading of the T cell with intracellular cholesterol. (c) These observations have built the concept of an increasing replacement of (athero-) protective immunity with a pro-atherogenic response.

Figure 4:. Distinct role of B cells in atherosclerosis.

B cells on a developmental stage (Pre-B) turn into innate-like B1 cells or adaptive, conventional B2 cells (right panel). B1 cells recognize epitopes on LDL and oxLDL particles, which leads to their activation and expression of low-affinity IgM antibodies by proliferation. Often, these IgM show cross-reactivity with epitopes on bacteria such as Streptococcus pneumoniae or on apoptotic cells. Interfering with B1 functionality aggravates atherosclerosis. B2 cells require co-stimulation by T_FH cells by MHC-II:peptide:TCR interactions and co-stimulatory signaling events to fully differentiate into plasma cells that express high-affinity IgG antibodies against atherogenic antigens, such as ApoB, oxLDL, or heat-shock proteins (HSP). Neutralizing B2 cells is atheroprotective, while the role of IgG-antibodies remains controversial with reported pro- and anti-atherogenic functions. Independent of the classification of B1/2 cells, distinct B cell subsets have been shown to express non-exclusive sets of cytokines, which allows the definition of cytokine-secreting B-effector (Be) −1 and −2 cells, regulatory B cells (B_regs), and innate-response activator (IRA) B cells (left panel).