Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • 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
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
PD-L1 negatively regulates CD4+CD25+Foxp3+ Tregs by limiting STAT-5 phosphorylation in patients chronically infected with HCV
Debora Franceschini, … , Mario U. Mondelli, Vincenzo Barnaba
Debora Franceschini, … , Mario U. Mondelli, Vincenzo Barnaba
Published February 23, 2009
Citation Information: J Clin Invest. 2009;119(3):551-564. https://doi.org/10.1172/JCI36604.
View: Text | PDF
Research Article

PD-L1 negatively regulates CD4+CD25+Foxp3+ Tregs by limiting STAT-5 phosphorylation in patients chronically infected with HCV

  • Text
  • PDF
Abstract

CD4+CD25+Foxp3+ Tregs suppress autoimmune responses. In addition, they limit T cell responses during chronic infection, thereby minimizing T cell–dependent immunopathology. We sought to investigate how Tregs are regulated in the livers of patients chronically infected with HCV, where they control the balance between an adequate protective immune response and suppression of immunopathology. We found that, despite accumulating and proliferating at sites of infection in the livers of patients chronically infected with HCV, Tregs were relatively less expanded than CD4+CD25+Foxp3– effector T cells. The relative lower expansion of intrahepatic Tregs coincided with their upregulation of programmed death–1 (PD-1). PD-1 expression inversely correlated with both Treg proliferation and clinical markers of immune suppression in vivo. Consistent with the possibility that PD-1 controls Tregs, blockade of the interaction between PD-1 and programmed death–1 ligand 1 (PD-L1) enhanced the in vitro expansion and function of Tregs isolated from the livers of patients chronically infected with HCV. Blockade of the interaction between PD-L1 and B7.1 also improved the proliferation of these cells. Interestingly, both PD-1 and phosphorylated STAT-5 were overexpressed in intrahepatic Tregs in a parallel fashion in steady disease conditions, and in an alternate-fluctuating fashion during the course of severe hepatitis reactivation. Notably, PD-L1 blockade upregulated STAT-5 phosphorylation in Tregs ex vivo. These data suggest that PD-L1 negatively regulates Tregs at sites of chronic inflammation by controlling STAT-5 phosphorylation.

Authors

Debora Franceschini, Marino Paroli, Vittorio Francavilla, Melissa Videtta, Stefania Morrone, Giancarlo Labbadia, Antonella Cerino, Mario U. Mondelli, Vincenzo Barnaba

×

Figure 6

PD-L1 blockade enhances IL-2–dependent proliferation of HCV-specific Tregs.

Options: View larger image (or click on image) Download as PowerPoint
PD-L1 blockade enhances IL-2–dependent proliferation of HCV-specific Tre...
(A) Single representative of 5 experiments, in which purified CFSE-labeled CD4+CD25+ Tregs from an HCV patient were stimulated with APCs alone or HCV-Ags/APCs and cocultured in a transwell plate system (denoted by lines) with Tresps that were stimulated or not with anti-CD3/CD28 in the presence or absence of anti–IL-2 mAb. In some cocultures, anti–HLA class I or –HLA class II mAb was added to the wells containing antigen-stimulated Tregs. After 6 d, cells were stained with mAbs to CD4, CD25, and Foxp3. Dot plot analyses are gated on CD4+CD25+ cells and show cells stained with both CFSE and anti-Foxp3. The percentage of cells is indicated in each quadrant. (B) Single representative of all the experiments shown in C, in which CFSE-labeled Tregs from an HCV patient were stimulated with APCs alone or HCV-Ags/APCs in the presence or absence (isotype control) of anti–PD-L1 mAb and/or Tresps. After 6 d, cells were stained with mAbs to CD4, CD25, and Foxp3. Dot plot analyses are gated on CD4+CD25+ cells and show cells stained with both CFSE and anti-Foxp3. The percentage of cells is indicated in each quadrant. (C) Percentage of CFSE-labeled Foxp3+ cells in Tregs upon antigen stimulation in the presence or absence of anti–PD-L1 and/or Tresps. Statistical analyses were performed with nonparametric Mann-Whitney U test for paired data. **P < 0.0040. Each symbol represents a single individual.

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

Sign up for email alerts