Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
Intrinsic TGF-β signaling promotes age-dependent CD8+ T cell polyfunctionality attrition
Rajarshi Bhadra, … , Ioannis Eleftherianos, Imtiaz A. Khan
Rajarshi Bhadra, … , Ioannis Eleftherianos, Imtiaz A. Khan
Published April 24, 2014
Citation Information: J Clin Invest. 2014;124(6):2441-2455. https://doi.org/10.1172/JCI70522.
View: Text | PDF
Research Article Immunology

Intrinsic TGF-β signaling promotes age-dependent CD8+ T cell polyfunctionality attrition

  • Text
  • PDF
Abstract

Advanced age is associated with immune system deficits that result in an increased susceptibility to infectious diseases; however, specific mediators of age-dependent immune dysfunction have not been fully elucidated. Here we demonstrated that aged mice exhibit poor effector CD8+ T cell polyfunctionality, primarily due to CD8+ T cell–extrinsic deficits, and that reduced CD8+ T cell polyfunctionality correlates with increased susceptibility to pathogenic diseases. In aged animals challenged with the parasite Encephalitozoon cuniculi, effector CD8+ T cell survival and polyfunctionality were suppressed by highly elevated TGF-β1. Furthermore, TGF-β depletion reduced effector CD8+ T cell apoptosis in both young and aged mice and enhanced effector CD8+ T cell polyfunctionality in aged mice. Surprisingly, intrinsic blockade of TGF-β signaling in CD8+ T cells was sufficient to rescue polyfunctionality in aged animals. Together, these data demonstrate that low levels of TGF-β1 promote apoptosis of CD8+ effector T cells and high TGF-β1 levels associated with age result in both CD8+ T cell apoptosis and an altered transcriptional profile, which correlates with loss of polyfunctionality. Furthermore, elevated TGF-β levels are observed in the elderly human population and in aged Drosophila, suggesting that TGF-β represents an evolutionarily conserved negative regulator of the immune response in aging organisms.

Authors

Rajarshi Bhadra, Magali M. Moretto, Julio C. Castillo, Constantinos Petrovas, Sara Ferrando-Martinez, Upasana Shokal, Manuel Leal, Richard A. Koup, Ioannis Eleftherianos, Imtiaz A. Khan

×

Figure 1

Attrition of effector CD8+KLRG1+ T cells in E. cuniculi–challenged aged mice.

Options: View larger image (or click on image) Download as PowerPoint
Attrition of effector CD8+KLRG1+ T cells in E. cuniculi–challenged aged ...
(A) Young mice were orally infected with E. cuniculi spores, and KLRG1 expression was assessed at day 12 after infection in IFN-γ+Gzb+ splenic CD8+ T cells. (B–D) Frequency (B and C) and absolute number (D) of CD8+KLRG1+ T cells in E. cuniculi–challenged animals at 2, 12, 14, and 21 months of age. (E and F) KLRG1+ CD8+ kinetic was assessed in young and 14-month-old mice at days 0, 6, 12, and 21 after infection. Data represent 2 experiments with at least 4 mice per group. Numbers in dot plots and histograms denote percentages.
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts