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

GP96 is a GARP chaperone and controls regulatory T cell functions

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 4

Increased turnover of Tregs and their compromised in vitro suppressive function in the absence of GP96.

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Increased turnover of Tregs and their compromised in vitro suppressive f...
(A) IC Ki-67 stain of CD4+FOXP3GFP+ Tregs and quantification of the ratio of Ki-67–positive cells in total Tregs. Data are representative of 2 independent experiments. Two-tailed Student’s t test was used for comparisons of different experimental groups. (B) Treg apoptosis was assayed by active caspase-3 staining. Numbers represent percentages of active caspase-3+ cells among total Tregs. Data are representative of 2 independent experiments. Two-tailed Student’s t test was used for comparisons between Het and KO mice. (C) Suppression of proliferation of CFSE-labeled CD4+CD25– T cells by splenic CD4+CD25+ T cells from KO mice and control littermates. Percentages of CFSElo in the population of all CD4+ cells are indicated. Five individual experiments were performed with similar findings.