Cited by 146T-cell and B-cell ImmunologyNeutrophil, Myeloperoxidase and Oxidative MechanismsAtherosclerosis and Cardiovascular Diseases

NADPH oxidase deficiency underlies dysfunction of aged CD8+ Tregs

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Wen, Zhenke, Shimojima, Yasuhiro, Shirai, Tsuyoshi, Li, Yinyin, Ju, Jihang, Yang, Zhen, Tian, Lu, Goronzy, Jörg J. +1 more·2016·Journal of Clinical Investigation

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.

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  • CD45RA+CCR7+NOX-2+ naive-like CD8+ Treg cells decline with age.

    “the population of CD45RA+CCR7+NOX-2+ naive-like CD8+ Treg cells declines with age”

    From Successful and Maladaptive T Cell Aging (2017) · cites this paper as Wen et al., 2016

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Authors
Wen, Z., Shimojima, Y., Shirai, T., Li, Y., Ju, J., Yang, Z., Tian, L., Goronzy, J. J., & Weyand, C. M.
Affiliations
Stanford Medicine (US)
Venue
Journal of Clinical Investigation
Published
2016-04-18
Volume
126
Issue
5
Pages
1953-1967
ISSN
  • 0021-9738 (ISSN-L)
  • 1558-8238
OpenAlex
W2338047394
Cited by
146
References
68
Citations by year
2026: 10 · 2025: 14 · 2024: 12 · 2023: 9 · 2022: 19 · 2021: 15 · 2020: 11 · 2019: 19 · 2018: 6 · 2017: 27 · 2016: 4
FWCI
11.32
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Veterans Affairs (I01 BX001669)
  • National Institutes of Health (AI108906, AI044142, HL058000)
  • Stanford Bio-X
  • National Institute on Aging (R01AG045779)
  • National Heart, Lung, and Blood Institute (P01HL058000, R01HL117913)
  • National Institute of Allergy and Infectious Diseases (R01AI044142, R01AI108906, R01AI108891, U19AI057266)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR042527)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
Keywords
NADPH oxidase 2, CD8+ regulatory T cells, CCR7, immunosenescence, giant cell arteritis, large-vessel vasculitis, T cell suppression, exosomes, CD4+ T cell proliferation
MeSH terms
NADPH Oxidase 2, Adult, Aged, Aged, 80 and over, Aging, Female, Humans, Male, Membrane Glycoproteins, Middle Aged, Giant Cell Arteritis, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, NADPH Oxidases, Receptors, CCR7, Exosomes

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