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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 9

Overexpression of NOX2 rescues the suppressive activity of old CD8 Tregs.

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Overexpression of NOX2 rescues the suppressive activity of old CD8 Tregs...
CD8 Tregs were induced from older individuals and transfected with a control or NOX2 expression vector. (A and B) Surface expression of NOX2 was evaluated 24 hours after transfection by flow cytometry. (A) One representative image and (B) results (mean ± SD) from 3 independent experiments are shown. (C) CD8 Tregs transfected with NOX2 expression vector or a control vector were analyzed for their suppressive function by mixing them with naive CD4 T cells and quantifying stimulation-induced pZAP70. Frequencies of pZAP70+ CD4 T cells (mean ± SD) from 10 independent experiments are shown. (D and E) Old CD8 Tregs were transfected with a control or NOX2 expression vector and tested for in vivo–suppressive activity by injecting them into NSG mice that had been reconstituted with naive CD4 T cells and monocytes. Nine days after transfer, expansion of CD4 T cells was quantified by enumerating the frequency and total numbers of human CD4 T cells in the murine spleen. Results are shown as mean ± SD from 6 independent experiments. (F–H) Old transfected CD8 Tregs were examined for in vivo function, as above. CD4 T cells were labeled with CFSE prior to the transfer. Proliferation of CD4 T cells was assessed by flow cytometric analysis of CFSE dilution in splenocytes harvested after 9 days. A representative image is shown, and results from 6 independent experiments are summarized as (mean ± SD) division index and proliferation index. 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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