Excessive interleukin-15 transpresentation endows NKG2D+CD4+ T cells with innate-like capacity to lyse vascular endothelium in granulomatosis with polyangiitis (Wegener's).

Abstract

OBJECTIVE Granulomatosis with polyangiitis (Wegener's) (GPA) is a rare systemic vasculitis of unknown etiology. Contribution of T cell-mediated immunity is suggested by the presence of granulomatous inflammation and T cell infiltrates in different tissues. We undertook this study to determine whether CD4+ T cells aberrantly expressing the NKG2D activating receptor might participate in the pathophysiology of the disease. METHODS We performed a detailed phenotype and functional analysis of CD4+ T cells in a cohort of 90 GPA patients (37 with localized GPA and 53 with generalized GPA) in comparison with 39 age-matched controls. RESULTS We observed circulating innate-like CD4+ T cells expressing an assortment of activating natural killer (NK) cell receptors (NKG2D, 2B4, DNAX-associated molecule 1, and some killer cell Ig-like receptors) and their signaling partners. Expansions of NKG2D+CD4+ T cells greater than a critical threshold of 3% yielded 100% specificity for generalized vasculitis versus localized granulomatosis, suggesting their participation in endothelium damage. Excessive interleukin-15 (IL-15) transpresentation through increased expression of IL-15 receptor α (IL-15Rα), together with abnormal expression of major histocompatibility complex (MHC) class I chain-related A protein on monocyte/macrophages, induced abnormal expansion of NKG2D+CD4+ T cells. These cells were primed in vivo to exert direct, MHC-independent cytotoxicity toward microvascular endothelial cells expressing the cognate ligands of NK cell receptors. CONCLUSION Our results suggest that NK cell-like CD4+ T cells might be the driving force of the vasculitis in GPA, and point to IL-15 as an important mediator in the progression of GPA toward generalized vasculitis. IL-15/IL-15Rα antagonists may thus become novel therapeutic tools to decrease the pool of NK cell receptor-positive CD4+ T cells in selected GPA patients.

DOI: 10.1002/art.30355
020406020132014201520162017
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@article{Menthon2011ExcessiveIT, title={Excessive interleukin-15 transpresentation endows NKG2D+CD4+ T cells with innate-like capacity to lyse vascular endothelium in granulomatosis with polyangiitis (Wegener's).}, author={Mathilde de Menthon and Marion Lambert and Elsa Guiard and Sara Tognarelli and B Bienvenu and Alexandre Karras and Loic P Guillevin and Sophie Caillat-Zucman}, journal={Arthritis and rheumatism}, year={2011}, volume={63 7}, pages={2116-26} }