GP96: safeguarding Treg

FOXP3 positive regulatory T cells (Tregs) are key players in maintaining peripheral immune tolerance. Multiple molecules and signaling pathways are involved in regulating Treg function. Understanding these mechanisms is vital to designing Treg-targeted immunotherapeutic strategies for cancer and other diseases. A recent study uncovered that endoplasmic reticulum resident chaperone, gp96, is essential for the function of Tregs. Genetic depletion of gp96 in Treg lineage leads to uncontrolled fatal inflammation. Mechanistically, gp96 safeguards Treg suppressive function by maintaining FOXP3 stability and regulating cell surface TGF-β bioavailability [1]. Tregs express a master transcription factor FOXP3 that controls their lineage stability and function. Although controversial, recent studies have suggested that Tregs may retain lineage plasticity, which is, the ability to switch their cell fate to various effector T cell types under circumstances such as inflammation [2]. gp96 is an essential chaperone for Toll-like receptors (TLRs) and integrins. When hsp90b1 (encoding gp96) was deleted conditionally using FOXP3-driven cre, FOXP3 expression decreased significantly [1]. Using a cell transfer model [2], it was found that highly purified (>99%) gp96-null Tregs dynamically lose FOXP3 expression and convert to IFN-γ producing T effector cells in the lymphopenic environment, despite the fact that Treg-specific demethylated region (TSDR) in the FOXP3 promoter was persistently demethylated [1]. Further studies unveiled that gp96 unexpectedly regulates TGF-β bioavailability on the cell surface. Three forms of TGF-β have been identified: soluble and active TGF-β, latent TGF-β associated with latent TGF-β binding protein (LTBP) and the membrane latent form of TGF-β (mLTGF-β). In Tregs, mLTGF-β is highly expressed and associated to the presence of mLTGF-β docking protein, Editorial