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

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 w...

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Bibliographic Details
Published in:Arthritis & rheumatology (Hoboken, N.J.) N.J.), 2011-07, Vol.63 (7), p.2116-2126
Main Authors: de Menthon, Mathilde, Lambert, Marion, Guiard, Elsa, Tognarelli, Sara, Bienvenu, Boris, Karras, Alexandre, Guillevin, Loïc, Caillat‐Zucman, Sophie
Format: Article
Language:English
Subjects:
Adolescent
Adult
Aged
Aged, 80 and over
Antibodies, Antineutrophil Cytoplasmic - immunology
Antibodies, Antineutrophil Cytoplasmic - metabolism
Biological and medical sciences
CD4-Positive T-Lymphocytes - immunology
CD4-Positive T-Lymphocytes - metabolism
CD4-Positive T-Lymphocytes - pathology
Cytotoxicity, Immunologic
Diseases of the osteoarticular system
Endothelium
Endothelium, Vascular - immunology
Endothelium, Vascular - metabolism
Endothelium, Vascular - pathology
Female
Flow Cytometry
Granulomatosis with Polyangiitis - immunology
Granulomatosis with Polyangiitis - metabolism
Granulomatosis with Polyangiitis - pathology
Humans
Immune system
Immunity, Cellular
Immunohistochemistry
Interleukin-15 - pharmacology
Lymphocytes
Male
Medical sciences
Middle Aged
NK Cell Lectin-Like Receptor Subfamily K - metabolism
Receptors, Interleukin-15 - metabolism
T cell receptors
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Summary: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.
ISSN:0004-3591
2326-5191
1529-0131
2326-5205
DOI:10.1002/art.30355