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
GP96 is a GARP chaperone and controls regulatory T cell functions
Yongliang Zhang, … , Bei Liu, Zihai Li
Yongliang Zhang, … , Bei Liu, Zihai Li
Published January 20, 2015
Citation Information: J Clin Invest. 2015;125(2):859-869. https://doi.org/10.1172/JCI79014.
View: Text | PDF
Research Article Immunology Article has an altmetric score of 1

GP96 is a GARP chaperone and controls regulatory T cell functions

  • Text
  • PDF
Abstract

Molecular chaperones control a multitude of cellular functions via folding chaperone-specific client proteins. CD4+FOXP3+ Tregs play key roles in maintaining peripheral tolerance, which is subject to regulation by multiple molecular switches, including mTOR and hypoxia-inducible factor. It is not clear whether GP96 (also known as GRP94), which is a master TLR and integrin chaperone, controls Treg function. Using murine genetic models, we demonstrated that GP96 is required for Treg maintenance and function, as loss of GP96 resulted in instability of the Treg lineage and impairment of suppressive functions in vivo. In the absence of GP96, Tregs were unable to maintain FOXP3 expression levels, resulting in systemic accumulation of pathogenic IFN-γ–producing and IL-17–producing T cells. We determined that GP96 serves as an essential chaperone for the cell-surface protein glycoprotein A repetitions predominant (GARP), which is a docking receptor for latent membrane–associated TGF-β (mLTGF-β). The loss of both GARP and integrins on GP96-deficient Tregs prevented expression of mLTGF-β and resulted in inefficient production of active TGF-β. Our work demonstrates that GP96 regulates multiple facets of Treg biology, thereby placing Treg stability and immunosuppressive functions strategically under the control of a major stress chaperone.

Authors

Yongliang Zhang, Bill X. Wu, Alessandra Metelli, Jessica E. Thaxton, Feng Hong, Saleh Rachidi, Ephraim Ansa-Addo, Shaoli Sun, Chenthamarakshan Vasu, Yi Yang, Bei Liu, Zihai Li

×

Figure 5

Failure of GP96 KO Tregs to suppress T cell–mediated autoimmune diseases.

Options: View larger image (or click on image) Download as PowerPoint
Failure of GP96 KO Tregs to suppress T cell–mediated autoimmune diseases...
(A) 6 × 106 CD25+ T cell–depleted splenocytes from diabetogenic NOD mice were adoptively transferred into NOD Rag–/– mice, along with purified WT or KO Tregs. After transfer, blood glucose was monitored kinetically. (B and C) Analysis of CD4+CD44hiCD62Llo cells in the pancreatic draining LNs of the recipient mice. Two-tailed Student’s t test was used for statistic analysis. One of the 3 representative experiments is shown. (D) H&E staining of pancreatic sections from the recipient mice 2 weeks after the adoptive transfer. (E–H) Suppression of colitis. (E) CD4+CD25–CD45Rbhi T cells isolated from pooled spleen and LNs of NOD mice were transferred i.v. into NOD Rag–/– mice along with either WT or KO Tregs. After transfer, the body weight of the recipient mice was examined weekly. Data represent 2 independent experiments. (F) H&E staining of colon section from the mice 6 weeks after T cell transfer. (G and H) Rescue of autoimmune colitis by WT BM cells. BM cells from WT or KO mice or mixture of the 2 (WT/KO = 1:1) were transfused into lethally irradiated recipients (NOD Rag–/– mice) followed by weekly examination. (G) Body weight. (H) Survival. Data represent results from 3 independent experiments. In experiments depicted in E–H, 2-way ANOVA was used for determining statistical significance on the body weight change; a log-rank (Mantel-Cox) test was used for statistical analysis of mouse survival.

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

Sign up for email alerts

Posted by 1 X users
66 readers on Mendeley
See more details