RESEARCH HIGHLIGHTS Nature Reviews Rheumatology 7, 314 (2011); doi:10.1038/nrrheum.2011.64 VASCULITIS SYNDROMES T cells turned killer by IL-15 attack the endothelium in GPA A subpopulation of CD4+ T cells in NKG2-D+ CD28– CD4+ T cells in MHC-independent lytic capacity toward patients with granulomatosis with rheumatoid arthritis, and the presence of vascular endothelial cells. Finally, we polyangiitis (GPA, formerly Wegener’s CD28– CD4+ T cells in the granulomatous found that these cells were expanded and vasculitis) expresses a receptor usually lesions of GPA. activated by IL-15.” found on natural killer (NK) cells, clonally With phenotypic and functional analysis Macrophages (a major cellular expands in response to IL-15, and aquires of CD4+ T cells from 90 patients with component of the granuloma in GPA) an NK-like phenotype. Cytotoxic to GPA (some with localized and others express IL-15, and the researchers propose vascular endothelial cells, this T-cell subset with generalized inflammation) and 39 that generalized GPA develops in two might be responsible for the vascular age-matched controls, the researchers steps: granuloma formation triggered injury that occurs in the patients with found not only that the proportion of by an unknown antigen involves clonal GPA in whom localized granulomatous NKG2-D+ CD4+ T cells was increased expansion of antigen-specific CD4+ inflammation progresses into diffuse in the people with GPA, but also, in T cells, which then become NK-like vasculitis, report Sophie Caillat-Zucman quantifying the expansion, that a cutoff in some patients as a consequence of et al. The pathogenesis of GPA, and why value of 3% NKG2-D+ CD4+ T cells gave excessive IL-15 trans-presentation within it sometimes progresses to diffuse disease, 100% specificity (and 45.3% sensitivity) the granuloma. Thus, the IL-15 pathway are largely unknown. for those with generalized vasculitis. might provide new therapeutic targets for Caillat-Zucman and colleagues study “We thus raised the hypothesis that these the treatment of generalized GPA. dysregulated signaling involving NKG2-D cells might be deleterious to the vascular Emma Leah type II integral membrane protein in endothelium”, says Caillat-Zucman. human disease, and the relationship Supporting this theory, other activating between activation of NKG2-D (which NK cell receptors and their signaling Original article de Menthon, M. et al. Excessive IL-15 itself activates NK cells) and aberrant partners were also found to be expressed transpresentation endows NKG2D+ CD4 T cells with expression of IL-15. They turned their by the cells. “Indeed,” continues Caillat- innate-like lytic capacity to vascular endothelium in focus to GPA after data from other groups Zucman, “we observed that NKG2-D+ Wegener’s vasculitis. Arthritis Rheum. doi:10.1002/ showed the presence of autoreactive CD4+ T cells behave as NK-like cells, with art.30355 NATURE REVIEWS | RHEUMATOLOGY VOLUME 7 | JUNE 2011 © 2011 Macmillan Publishers Limited. All rights reserved.