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Unraveling the identity of FoxP3+regulatory T cells in Granulomatosis with Polyangiitis patients

Reijnders, T. D. Y., Stegeman, C. A., Huitema, M. G., Rutgers, A., Heeringa, P. & Abdulahad, W. H., 4-Jun-2019, In : Scientific Reports. 9, 1, 9 p., 8273.

Research output: Contribution to journalArticleAcademicpeer-review

Human CD4(+)FoxP3(+)T-cells are heterogeneous in function and include not only suppressive cells (Tregs), but also effector cells that transiently express FoxP3 upon activation. Previous studies in Granulomatosis with Polyangiitis (GPA-) patients have demonstrated an increase in FoxP3(+)T-cells with impaired suppressive capacity and an increase in Th17 cells. We hypothesized that the increase in FoxP3(+)T-cells results from an increase in non-suppressive effector-like cells. The frequency of circulating CD4(+)FoxP3(+)T-cell subsets were determined by flow cytometry in 46 GPA-patients in remission and 22 matched healthy controls (HCs). Expression levels of FoxP3 and CD45RO were used to distinguish between CD45RO(-) FoxP3(low) resting Tregs (rTreg), CD45RO(+) FoxP3(high) activated Tregs (aTreg) and CD45RO(+)FoxP3(low) proinflammatory non-suppressive T-cells (nonTreg). Intracellular expression of IFN gamma, IL-17, and IL-21 was compared within these subsets. We found a significant increase in the frequency of nonTreg cells in GPA-patients as compared with HCs. Importantly, within the nonTreg subset, antineutrophil cytoplasmic autoantibody (ANCA-) positive patients demonstrated a significantly higher percentage of IL-17+ and IL-21+ cells when compared with ANCA-negative patients and HCs. Moreover, expanded nonTregs from ANCA-positive patients induced excessive proliferation of responder cells in vitro and exhibited higher IL-21 production. Production of IL-17 and IL-21 in non-suppressive FoxP3+T-cells may point toward a pathogenic role in ANCA formation.

Original languageEnglish
Article number8273
Number of pages9
JournalScientific Reports
Volume9
Issue number1
Publication statusPublished - 4-Jun-2019

    Keywords

  • WEGENERS-GRANULOMATOSIS, DISEASE-ACTIVITY, B-CELLS, IL-21, ANCA, VASCULITIS, AUTOANTIBODIES, ACTIVATION, TREG, TH17

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