ApoB-Specific CD4+ T Cells in Mouse and Human Atherosclerosis

Abstract

Atherosclerosis is a chronic inflammatory condition of the arterial wall that leads to the formation of vessel-occluding plaques within the subintimal space of middle-sized and larger arteries. While traditionally understood as a myeloid-driven lipid-storage disease, growing evidence suggests that the accumulation of low-density lipoprotein cholesterol (LDL-C) ignites an autoimmune response with CD4+ T-helper (TH) cells that recognize self-peptides from Apolipoprotein B (ApoB), the core protein of LDL-C. These autoreactive CD4+ T cells home to the atherosclerotic plaque, clonally expand, instruct other cells in the plaque, and induce clinical plaque instability. Recent developments in detecting antigen-specific cells at the single cell level have demonstrated that ApoB-reactive CD4+ T cells exist in humans and mice. Their phenotypes and functions deviate from classical immunological concepts of distinct and terminally differentiated TH immunity. Instead, ApoB-specific CD4+ T cells have a highly plastic phenotype, can acquire several, partially opposing and mixed transcriptional programs simultaneously, and transit from one TH subset into another over time. In this review, we highlight adaptive immune mechanisms in atherosclerosis with a focus on CD4+ T cells, introduce novel technologies to detect ApoB-specific CD4+ T cells at the single cell level, and discuss the potential impact of ApoB-driven autoimmunity in atherosclerosis.

Modulating Autoimmunity against LDL: Development of a Vaccine against Atherosclerosis

“… 13 14 The activation of CD4 + T cells in the plaque requires antigen presentation on MHC-II by antigen-presenting cells (APCs), such as dendritic cells or plaque macrophages. 5 11 15 Antigen recognition, along with costimulatory signals from the APC, promotes the differentiation and activation of T H cells. 16 As a result, naive T cells develop into effector T (T eff ) cells that express distinct intracellular transcription factors and cytokines.…”

“…They show signs of chronic activation, have a predominant effector-memory phenotype, and express known T-cell activation markers, including CD69, CD38, granzyme, and others, suggestive of repetitive antigen exposure by cognate, either self - or foreign antigens. 11 14 32 CD4 + T cells in human plaques show increased expression of programmed cell death protein 1 (PD-1) that is typically upregulated in chronically stimulated and exhausted T cells and prevents cell activation. 14 These findings suggest that a natural counterregulatory checkpoint, which protects from ongoing autoimmunity, exists in atherosclerosis.…”

“… 46 An explanation sparked by more recent findings is that the autoreactive response in atherosclerosis is heterogeneous, subtype- and context-dependent, and can be pro- and anti-inflammatory (immune activating and immunosuppressive) at the same time, which may explain an overall neutral net effect in Rag1 −/− mice. 5 11 Indeed, ApoB-reactive T helper cells in the early stages of atherosclerosis seem to be immunosuppressive. 27 Likewise, genetic abrogation of MHC-II-dependent antigen presentation aggravates atherosclerosis.…”

“… 7 9 Besides the myeloid cellular response, LDL-C initiates an autoimmune response in atherosclerotic plaques with autoreactive CD4 + T-helper cells and B-cell-derived autoantibodies that target LDL and its core protein, apolipoprotein B (ApoB). 5 10 11 The modulation of this autoimmune response with immunomodulatory vaccination strategies has been increasingly investigated in the last decades. Here, we present and discuss the development of a vaccine against atherosclerosis.…”

Inflammation and Atherosclerosis

“…Treg instability refers to the eventual loss of the Treg-defining transcription factor FoxP3. Timoteo Marchini, Sophie Hansen and Dennis Wolf wrote a very up-to-date review on “ApoB-Specific CD4+ T Cells in Mouse and Human Atherosclerosis”, an emerging area of research that also holds promise for translation [ 7 ]. They discuss the CD4 T cell lineages (Th1, 2, 9, 17 and 22, Tregs, follicular helper T cells, cytotoxic CD4 T cells and CD4+ NKT cells).…”