T cells in arteritis and atherosclerosis

Abstract

Purpose of review: Inflammatory vasculopathies, spanning from atherosclerosis to vasculitides, are driven by innate and adaptive immune responses. Instructed by antigen-presenting cells, T cells have unsurpassed skills to orchestrate protective and pathogenic immunity. Pro-inflammatory and anti-inflammatory T cells regulate master pathogenic pathways, providing a framework for novel immunotherapeutic strategies.

Recent findings: The multilayered wall of macrovessels creates a unique tissue niche; professional antigen-presenting cells, specifically dendritic cells, are superior in triggering and maintaining T-cell responses in this tissue milieu. Plaque-residing dendritic cells sense pathogen-derived motifs and edit inflammatory responses. T cells respond to antigen but antigen-nonspecific factors setting cellular response thresholds may be equally important. Dysregulated signal transduction pathways emerge as highly relevant in biasing T cells toward hyperresponsiveness. In the inflamed atheroma and in arteritic lesions, pathogenic T cells coordinate multiple injury pathways. Besides inducing tissue-damaging macrophage functions, they directly inflict cellular injury within the arterial wall. Distinctively, selected T cells induce smooth muscle cell apoptosis, most prominently by upregulating the death-receptor ligand TRAIL.

Summary: Innate sentinels, specifically dendritic cells, populate normal arteries, intramural vasculitic lesions, and the inflamed atheroma. They sense microbial motifs and instruct T cells toward pro-inflammatory and tissue-destructive effector functions. Microenvironmental factors imposed by the unique structure of the arterial wall appear to be highly conserved across disease entities, modulating inflammation in atherosclerosis and arteritis.

Figure 1. Antigen-presenting Cells as Key Players in Vascular Inflammation

Figure 1A: Dendritic Cells are Superior Antigen-presenting Cells in the Vessel Wall. To directly compare the capacity of different types of antigen-presenting cells to sense danger signals and initiate adaptive T-cell responses, human bioarteries were engineered to contain monocytes, macrophages, or myeloid dendritic cells, respectively. After exposure to microbial motifs (LPS), recruitment and intra-wall activation of autologous T cells were quantified. Monocytes had no APC function. Macrophages recruited low numbers of T cells but failed to activate them. Dendritic cells were highly efficient in attracting T cells and facilitating their in-situ activation. Figure 1B: Myeloid and Plasmacytoid Dendritic Cells Regulate Inflammation in the Atherosclerotic Plaque. Myeloid and plasmacytoid DC populate the inflamed human atheroma. Each type of DC utilizes a distinct profile of pattern recognition receptors and produces a unique cocktail of immunoregulatory cytokines. The signature cytokine of pDC is type I interferon which directly regulates T-cell effector functions by inducing the death ligand TRAIL. Type 1 interferon also amplifies the production of pro-inflammatory cytokines and proteases in mDC and macrophages. (Reproduced from ref. , copyright owner Lippincott, Williams & Wilkins, 2007, with permission.)

Figure 2. Antigen-nonspecific signals determine T-cell response thresholds

Recognition of specific antigen is a critical factor in initiating T-cell stimulation. However, the intensity of the activation cascade is modulated by numerous additional signals, including positive and negative amplification loops functioning in the cytoplasm. Such signals may be as important as antigen in determining whether, when, and where T cells in the microenvironment of the vascular wall are activated.

Figure 3. Tissue-injurious effector functions of T cells in the vascular wall

T cells cause tissue injury in the vascular wall through numerous pathways. They orchestrate the function of other inflammatory cells, leading to the release of proteases, reactive oxygen intermediates, cytokines, and growth factors. Alternatively, T cells function as effector cells directly damaging wall-residing cells and matrices. Of particular interest are cytotoxic CD4 T cells that kill VSMC by triggering the death pathway, weakening the tissue scaffold.