Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • 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 ...
    • Aging (Upcoming)
    • Next-Generation Sequencing in Medicine (Jun 2022)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • Gut-Brain Axis (Jul 2021)
    • Tumor Microenvironment (Mar 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • 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
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
Wiskott-Aldrich syndrome protein is required for regulatory T cell homeostasis
Stephanie Humblet-Baron, … , Daniel J. Campbell, David J. Rawlings
Stephanie Humblet-Baron, … , Daniel J. Campbell, David J. Rawlings
Published February 1, 2007
Citation Information: J Clin Invest. 2007;117(2):407-418. https://doi.org/10.1172/JCI29539.
View: Text | PDF
Research Article Immunology

Wiskott-Aldrich syndrome protein is required for regulatory T cell homeostasis

  • Text
  • PDF
Abstract

Wiskott-Aldrich syndrome protein (WASp) is essential for optimal T cell activation. Patients with WAS exhibit both immunodeficiency and a marked susceptibility to systemic autoimmunity. We investigated whether alterations in Treg function might explain these paradoxical observations. While WASp-deficient (WASp–/–) mice exhibited normal thymic Treg generation, the competitive fitness of peripheral Tregs was severely compromised. The total percentage of forkhead box P3–positive (Foxp3+) Tregs among CD4+ T cells was reduced, and WASp–/– Tregs were rapidly outcompeted by WASp+ Tregs in vivo. These findings correlated with reduced expression of markers associated with self-antigen–driven peripheral Treg activation and homing to inflamed tissue. Consistent with these findings, WASp–/– Tregs showed a reduced ability to control aberrant T cell activation and autoimmune pathology in Foxp3–/–Scurfy (sf) mice. Finally, WASp+ Tregs exhibited a marked selective advantage in vivo in a WAS patient with a spontaneous revertant mutation, indicating that altered Treg fitness likely explains the autoimmune features in human WAS.

Authors

Stephanie Humblet-Baron, Blythe Sather, Stephanie Anover, Shirly Becker-Herman, Debora J. Kasprowicz, Socheath Khim, Thuc Nguyen, Kelly Hudkins-Loya, Charles E. Alpers, Steve F. Ziegler, Hans Ochs, Troy Torgerson, Daniel J. Campbell, David J. Rawlings

×

Figure 1

WT Tregs are expanded in a WAS patient following reversion of a pathogenic mutation.

Options: View larger image (or click on image) Download as PowerPoint
WT Tregs are expanded in a WAS patient following reversion of a pathogen...
Peripheral blood mononuclear cells were analyzed by flow cytometry using antibodies to CD4, CD45RA, CD27, CD62L, WASp, and FOXP3. (A) Characterization of the CD4+FOXP3+ (Tregs) and CD4+FOXP3– (effector T cell [TEFF]) cell populations within the total lymphocyte gate. (B) WASp expression within the CD4+FOXP3+ Treg population demonstrating that approximately 25% of the patient’s Tregs are WASp+. (C) Identification of the naive CD4+CD27+CD45RA+ T cells within the CD4+FOXP3 TEFF cell population. Naive cells account for approximately 7% of the TEFF population in this patient. (D) Within the naive T cell compartment, only a small proportion of the cells (approximately 2%) are WASp+. (E) In comparison with the TEFF population, very few (<1%) CD27+CD45RA+ naive cells are present within the CD4+FOXP3+ Treg population. (F and G) Within the CD4+FOXP3+ Treg population, WASp+ cells account for equal percentages of the CD62L+ (F) and CD62L– (G) Treg subsets.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts