title: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: INSERM, U986, Hôpital Saint-Vincent de Paul, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: de Menthon
authors.forename: Marion
authors.initials: M
authors.lastname: Lambert
authors.forename: Elsa
authors.initials: E
authors.lastname: Guiard
authors.forename: Sara
authors.initials: S
authors.lastname: Tognarelli
authors.forename: Boris
authors.initials: B
authors.lastname: Bienvenu
authors.forename: Alexandre
authors.initials: A
authors.lastname: Karras
authors.forename: Loïc
authors.initials: L
authors.lastname: Guillevin
authors.forename: Sophie
authors.initials: S
authors.lastname: Caillat-Zucman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D003602:Cytotoxicity, Immunologic; D004730:Endothelium, Vascular / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D014890:Granulomatosis with Polyangiitis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007111:Immunity, Cellular; D007150:Immunohistochemistry; D019409:Interleukin-15 / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism*; D053647:Receptors, Interleukin-15 / Q000378:metabolism
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D019409:Interleukin-15; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D053647:Receptors, Interleukin-15