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 CD4 T 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 CD4 T cell compartment, resulting in wide-spread CD4 T 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.

Clinical and pathological evolution of giant cell arteritis: a prospective study of follow-up temporal artery biopsies in 40 treated patients

“… 21 Molecular analysis of the vasculitic lesions has demonstrated that multiple functional lineages contribute to the granulomatous infiltrates and that such functionally lineages are differentially susceptible to therapeutic interventions. 22 Specifically, IL-17-producing T-cells disappear from the lesions in steroid-treated patients, while IFN-γ-producing T-cells persist. 8 , 23 The multi functionality of vessel-wall residing T-cells questions the role of a single antigen in driving the misplaced immune response.…”

Cellular Signaling Pathways in Medium and Large Vessel Vasculitis

“…Multiple studies have shown that Th1 cells that produce interferon (IFN)-γ and Th17 cells that produce IL-17 participate in the vasculitic infiltrates (27)(28)(29)(30)(31). An expansion of Th1 and Th17 cells has also been reported for peripheral blood of GCA patients (27,32).…”

The immunoinhibitory PD-1/PD-L1 pathway in inflammatory blood vessel disease

“…Removing the PD‐1/PD‐L1–dependent protection lead to a dense T cell infiltrate, with T cells from multiple different lineages represented (Fig. ).…”

“…Cellular origins and processes giving rise to the growing intima are not entirely clear, but proceed at rapid pace in GCA . Arteries treated with the checkpoint inhibitor had markedly increased numbers of microvessels and the thickness of the intimal layer doubled . It is possible that removing negative signaling by PD‐1 blockade translated into much more aggressive inflammation, equally intensifying downstream events.…”