GP96 is a GARP chaperone and controls regulatory T cell functions

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• CD4+FOXP3+ regulatory T cells (Tregs) are crucial for peripheral tolerance.
• Treg function is regulated by molecular switches like mTOR and HIF.
• The role of GP96 (GRP94), a master chaperone for TLRs and integrins, in Treg biology was unclear.

Purpose of the Study:

• To investigate whether GP96 controls Treg function and maintenance.
• To elucidate the molecular mechanisms by which GP96 might regulate Tregs.

Main Methods:

• Utilized murine genetic models to study GP96 function in Tregs.
• Assessed Treg lineage stability and suppressive functions in vivo.
• Analyzed FOXP3 expression, T cell populations (IFN-γ, IL-17), and TGF-β pathway components.

Main Results:

• GP96 is required for Treg maintenance and in vivo suppressive function.
• GP96 deficiency leads to Treg instability and loss of FOXP3 expression.
• GP96 is an essential chaperone for GARP, a receptor for latent TGF-β.
• GP96 loss impairs mLTGF-β expression and active TGF-β production by Tregs.

Conclusions:

• GP96 is a critical regulator of Treg stability and immunosuppressive function.
• GP96 controls Treg biology by chaperoning GARP and facilitating TGF-β signaling.
• GP96 acts as a key molecular switch integrating stress responses with Treg-mediated immune tolerance.