Pro-inflammatory and anti-inflammatory T cells in giant cell arteritis

Abstract

Giant cell arteritis is an autoimmune disease defined by explicit tissue tropism to the walls of medium and large arteries. Pathognomic inflammatory lesions are granulomatous in nature, emphasizing the functional role of CD4T cells and macrophages. Evidence for a pathogenic role of antibodies and immune complexes is missing. Analysis of T cell populations in giant cell arteritis, both in the tissue lesions and in the circulation, has supported a model of broad, polyclonal T cell activation, involving an array of functional T cell lineages. The signature of T cell cytokines produced by vasculitic lesions is typically multifunctional, including IL-2, IFN-γ, IL-17, IL-21, and GM-CSF, supportive for a general defect in T cell regulation. Recent data describing the lack of a lymph node-based population of anti-inflammatory T cells in giant cell arteritis patients offers a fresh look at the immunopathology of this vasculitis. Due to defective CD8⁺NOX2⁺ regulatory T cells, giant cell arteritis patients appear unable to curtail clonal expansion within the CD4T cell compartment, resulting in widespread CD4T cell hyperimmunity. Why unopposed expansion of committed CD4 effector T cells would lead to invasion of the walls of medium and large arteries needs to be explored in further investigations.

Keywords: Anti-inflammatory T cells; CD8(+) Treg cells; Giant cell arteritis; Macrophage; Pro-inflammatory T cells.

Fig. 1. Multiple T helper cell lineages participate in GCA

CD4 T cells are the dominant cell population in the vasculitic lesions of GCA, where they partner with macrophages to build granulomatous infiltrates. Based on the production of signature cytokines, CD4 helper cell are subcategorized into distinct effector cell lineages. Vessel wall infiltrates in GCA patients are characterized by a broad array of T helper cell types, suggestive for a broad defect in T cell biology.

Fig. 2. Pro-inflammatory T cells in GCA

T cells accumulating in the granulomatous infiltrates of GCA are functionally diverse. Based on their cytokine production profile, such lesional T cells are able to interact with selected immune and nonimmune target cells and promote distinct pathogenic pathways. The best understood pathways are outlined. Available data suggest that additional T cell dependent pathogenic cascades are operational in the inflamed arterial wall.

Fig. 3. CD8⁺ CCR7⁺ FoxP3⁺ Treg as the missing link in GCA

Recently described CD8⁺ Treg cells suppress CD4 T cell responses by releasing microvesicles packaged with the NADPH oxidase NOX2, thereby controlling the activation of nearby CD4 T cells. NOX2-containing microvesicles are absorbed by CD4 T cells, where they inhibit membrane-proximal T cell receptor signaling events and effectively suppress CD4 T cell expansion and survival. Patients with GCA essentially have lost the ability to induce CD8⁺NOX2⁺ Tregs, disrupting control of the CD4 T cell compartment.

Fig. 4. Defects in central and peripheral immunoregulation in GCA

To prevent uncontrolled inflammation, antigen-specific T cells are subject to tolerance-inducing mechanisms both in central lymphoid organs as well as in peripheral tissue sites. Both sites need to be integrated into pathogenic models for GCA. Available data suggest that GCA vascular lesions are poor in anti-inflammatory T cells. Recent studies have revealed a defect in CD8 Tregs, which function in central lymphoid organs and are essentially absent in GCA patients.