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NADPH oxidase deficiency underlies dysfunction of aged CD8+ Tregs
Zhenke Wen, … , Jörg J. Goronzy, Cornelia M. Weyand
Zhenke Wen, … , Jörg J. Goronzy, Cornelia M. Weyand
Published April 18, 2016
Citation Information: J Clin Invest. 2016;126(5):1953-1967. https://doi.org/10.1172/JCI84181.
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Research Article Aging Immunology Article has an altmetric score of 47

NADPH oxidase deficiency underlies dysfunction of aged CD8+ Tregs

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Abstract

Immune aging results in progressive loss of both protective immunity and T cell–mediated suppression, thereby conferring susceptibility to a combination of immunodeficiency and chronic inflammatory disease. Here, we determined that older individuals fail to generate immunosuppressive CD8+CCR7+ Tregs, a defect that is even more pronounced in the age-related vasculitic syndrome giant cell arteritis. In young, healthy individuals, CD8+CCR7+ Tregs are localized in T cell zones of secondary lymphoid organs, suppress activation and expansion of CD4 T cells by inhibiting the phosphorylation of membrane-proximal signaling molecules, and effectively inhibit proliferative expansion of CD4 T cells in vitro and in vivo. We identified deficiency of NADPH oxidase 2 (NOX2) as the molecular underpinning of CD8 Treg failure in the older individuals and in patients with giant cell arteritis. CD8 Tregs suppress by releasing exosomes that carry preassembled NOX2 membrane clusters and are taken up by CD4 T cells. Overexpression of NOX2 in aged CD8 Tregs promptly restored suppressive function. Together, our data support NOX2 as a critical component of the suppressive machinery of CD8 Tregs and suggest that repairing NOX2 deficiency in these cells may protect older individuals from tissue-destructive inflammatory disease, such as large-vessel vasculitis.

Authors

Zhenke Wen, Yasuhiro Shimojima, Tsuyoshi Shirai, Yinyin Li, Jihang Ju, Zhen Yang, Lu Tian, Jörg J. Goronzy, Cornelia M. Weyand

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Figure 7

CD4 T cells uptake NOX2-containing exosomes released by CD8 Tregs.

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CD4 T cells uptake NOX2-containing exosomes released by CD8 Tregs.
(A) P...
(A) PKH67-labeled CD8 Tregs (green) and CellTracker Red–labeled naive CD4 T cells (red) were mixed for 60 minutes. Transfer of PKH67-labeled membranes from CD8 Tregs into CD4 T cells (yellow) was observed by live-cell microscopy. Scale bar: 5 μm. (B) Uptake of PKH67-labeled membrane fragments by CD4 T cells was analyzed by flow cytometry. A representative histogram of CD4 T cells that had or had not been in contact with PKH67-labeled CD8 Tregs cells is shown. (C) Frequencies of CD4 T cells that had taken up PKH67-labeled membrane fragments from CD8 Tregs. Results are from 3 independent experiments (mean ± SD). (D and E) Exosomes were isolated from the supernatant of PKH67-labeled CD8 Tregs and added into the culture of naive CD4 T cells at the indicated ratios for 60 minutes. The frequency of CD4 T cells that had taken up PKH67-containing exosomes was determined by flow cytometry. Results are presented as mean ± SD and are from 5 independent experiments. (F and G) Exosomes isolated from the supernatant of CD8 Tregs were stained with anti-human NOX2/gp91phox antibody and analyzed by flow cytometry. One representative image and results from 4 independent experiments (mean ± SD) are shown. (H and I) CD8 Tregs and CD8 Treg-derived exosomes were loaded with oxidation-sensitive fluorogens and analyzed by flow cytometry to detect ROS levels. Fresh CD8 T cells from the same donor were used as controls. Representative histograms and a summary of 7 independent experiments (mean ± SD) are shown. Unpaired 2-tailed Student’s t test was used for comparisons.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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