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Review
. 2020 Sep 25:11:587089.
doi: 10.3389/fimmu.2020.587089. eCollection 2020.

Cellular Signaling Pathways in Medium and Large Vessel Vasculitis

Ryu Watanabe  1 , Gerald J Berry  2 , David H Liang  1 , Jörg J Goronzy  1 , Cornelia M Weyand  1
Affiliations
Review

Cellular Signaling Pathways in Medium and Large Vessel Vasculitis

Ryu Watanabe et al. Front Immunol. .

Abstract

Autoimmune and autoinflammatory diseases of the medium and large arteries, including the aorta, cause life-threatening complications due to vessel wall destruction but also by wall remodeling, such as the formation of wall-penetrating microvessels and lumen-stenosing neointima. The two most frequent large vessel vasculitides, giant cell arteritis (GCA) and Takayasu arteritis (TAK), are HLA-associated diseases, strongly suggestive for a critical role of T cells and antigen recognition in disease pathogenesis. Recent studies have revealed a growing spectrum of effector functions through which T cells participate in the immunopathology of GCA and TAK; causing the disease-specific patterning of pathology and clinical outcome. Core pathogenic features of disease-relevant T cells rely on the interaction with endothelial cells, dendritic cells and macrophages and lead to vessel wall invasion, formation of tissue-damaging granulomatous infiltrates and induction of the name-giving multinucleated giant cells. Besides antigen, pathogenic T cells encounter danger signals in their immediate microenvironment that they translate into disease-relevant effector functions. Decisive signaling pathways, such as the AKT pathway, the NOTCH pathway, and the JAK/STAT pathway modify antigen-induced T cell activation and emerge as promising therapeutic targets to halt disease progression and, eventually, reset the immune system to reestablish the immune privilege of the arterial wall.

Keywords: NOTCH; T cells; Takayasu arteritis; co-stimulation; giant cell arteritis; immune checkpoint; large vessel vasculitis; macrophages.

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Figures

FIGURE 1
FIGURE 1
CD4+ and CD8+ T cells in Giant Cell Arteritis. Tissue sections from an ascending aortic aneurysm repair in a 66-year-old woman presenting with back pain in the mid-thoracic region. (A) High power magnification of the medial layer showing granulomatous inflammation surrounding depleted smooth muscle cells and necrotic elastic fibers (Hematoxylin and eosin ×200). (B) CD3 immunostaining showing numerous T cells within the medial infiltrates (×200). (C) CD4 immunostaining of T-helper cells at the edge of the granuloma (×200). (D) CD8 staining showing scarce T-cytotoxic cells within the T-cell rich inflammatory lesions (×200).
FIGURE 2
FIGURE 2
CD4+ and CD8+ T cells in Takayasu arteritis. Aneurysm of the aortic root and the aortic arch, complicated by aortic regurgitation in a 41-year-old female. (A) Necrotizing granulomatous inflammation composed of lymphocytes and multinucleated giant cells surrounding a zone of necrotic medial tissue (H&E ×200); (B) CD3+ T cells create an inflammatory collar around the zone of necrosis (×200); (C) CD4+ T-helper cells (×200) and (D) CD8+ T-cytotoxic cells (×200) comprise the majority of tissue-residing T-cells.
FIGURE 3
FIGURE 3
Defective CD8+ regulatory T cells in giant cell arteritis. Like CD4+ regulatory T cells, CD8+ regulatory T cells (CD8+ Treg) express the transcription factor FOXP3 and act as a suppressor of immune responses. CD8+ CCR7+ Tregs inhibit immunity by releasing exosomes that contain the enzyme NADPH oxidase 2 (NOX2). These exosomes are integrated into the membrane of neighboring CD4+ T cells, where they disrupt proximal signaling events, including the phosphorylation of ZAP70. CD8+ Tregs from patients with GCA are reduced in number and are functionally defective.
FIGURE 4
FIGURE 4
Activation pathways in pathogenic CD4+ T cells. Multiple signaling pathways contribute to the activation of pathogenic CD4+ T cells in giant cell arteritis. Antigen recognition by the T cell receptor triggers rapid division, differentiation and lineage commitment. CD28 receptor engagement co-stimulates, mediated through AKT phosphorylation and downstream activation of the mechanistic target of rapamycin complex 1 (mTORC1). Additional stimuli derive from metabolic signals. Glucose uptake is controlled through the expression of the glucose transporter 1 (GLUT1). Glycolytic breakdown generates pyruvate, which functions as a critical energy carrier for mitochondria, sustaining ATP production and the release of metabolic intermediates. Antigen-stimulated, metabolically active CD4+ T cells differentiate into effector cells secreting IFN-γ, IL-17, and IL-21 and sustain a vessel wall remodeling program resulting in wall vascularization and lumen-occlusive intimal hyperplasia.
FIGURE 5
FIGURE 5
The NOTCH signaling pathway in giant cell arteritis. A signature abnormality of CD4+ T cells in GCA is the aberrant expression of the NOTCH1 receptor. NOTCH1+ CD4+ T cells engage the JAGGED1 ligand on the surface of microvascular endothelial cells. Vascular endothelial growth factor (VEGF) in the circulation functions as the JAGGED1 inducer. Via HES1, the NOTCH signaling pathway activates the mechanistic target of rapamycin complex 1 (mTORC1). Persistent NOTCH signaling promotes T cell proliferation, invasion of CD4+ T cells into the vessel wall, upregulation of the metabolic program and differentiation into cytokine-producing effector cells.
FIGURE 6
FIGURE 6
Druggable signaling cascades in vasculitogenic T cells. Numerous signals converge to shape the activation patterns of T cells. In the case of vasculitis-inducing T cells, vasculitogenic antigens trigger the T cell receptor activation cascade. Several co-stimulatory signals adjust signal strength and duration and thus determine differentiation, effector functions and longevity of the T cell. CD28-dependent signaling regulates the metabolic program of vasculitogenic T cells. CD28-mediated signals activate mTORC1, thus determining T cell proliferation and lineage assignment. Persistent NOTCH signaling is a signature abnormality of vasculitogenic CD4+ T cells and regulates tissue invasiveness. Cytokines modulating T cell function utilize the JAK-STAT signaling pathway. Disease-relevant cytokine signals derive from IL-2, IL-7, and, possibly, from type 1 interferon.
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