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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.
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Research Article Immunology Article has an altmetric score of 1

GP96 is a GARP chaperone and controls regulatory T cell functions

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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

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Figure 8

GP96 controls mTGF-β bioactivity.

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GP96 controls mTGF-β bioactivity.
(A) MACS-purified CD4+CD25+ Tregs were...
(A) MACS-purified CD4+CD25+ Tregs were stimulated with plate-bound antibody against CD3 (1 μg/ml) and CD28 (0.5 μg/ml) for indicated times. TGF-β levels in the culture supernatant were quantitated by ELISA. Data represent 3 independent experiments. (B) CD4+CD25+ Tregs were stimulated with TGF-β1 (1 ng/ml) for 45 minutes or antibodies against CD3 and CD28 for 24 hours. Cells were then fixed and stained intracellularly for p-Smad2/3. Numbers indicate percentages of indicated cells in the entire population. Data represent 3 independent experiments. (C) CD4+CD25+ Tregs were activated with plate-bound anti-CD3 antibody (2 μg/ml) for 2 to 3 days, followed by irradiation (2000 cGy) and coculturing with CD4+CD25– naive T cells for 3 days, with or without RGD peptide. The level of IL-17A in the culture supernatant was determined by ELISA. Data represent 4 independent experiments. (D and E) 1 × 106 CD4+CD25– naive T cells from 3-week-old WT NOD or Hsp90b1fl/flCD4-Cre mice were transferred into NOD Rag–/– mice. Four weeks later, induced Tregs (CD4+CD25+FOXP3+) were examined by flow cytometry (D) and quantified (E) (each dot represents 1 individual mouse). Data represent 3 independent experiments. (F) Irradiated NOD Rag–/– recipient mice were transplanted with KO BM. Seven days later, mice were injected i.p. with recombinant TGF-β2 (0.2 μg/100 μl) daily for 5 days, followed by once every 3 days. Survival of the mice was monitored. Data represent 2 independent experiments. Statistical analyses were performed with 2-tailed Student’s t test for (A, C, and E) and log-rank test (F).

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