Induction of Foxp3 and Activation of Regulatory T Cells by Heat Shock Protein Gp96 for Treatment of Autoimmune Diseases

Abstract

Utilizing regulatory T cells (Treg) is a promising approach for treating autoimmune diseases, including systemic lupus erythematosus (SLE) and rheumatic diseases. Upregulation and stabilization of forkhead box P3 (Foxp3) expression in Tregs are essential for regulating Treg function and immune homeostasis. In this study, we examined the potential effect and mechanism of heat shock protein gp96 in regulating Foxp3 expression and Treg activation in vivo. High-dose gp96 immunization showed obvious therapeutic effects in a Lyn-/- mouse model of SLE, as evidenced by decreased auto-antibody titers, follicular helper T cells, and antibody-production plasma cells. Moreover, immunization of mice with gp96 alleviated the initiation and progression of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE). Immunization of gp96 increased Treg frequency, expansion, and suppressive function with no obvious effector T cell activation. Gene expression profiling was used to identify the NF-κB family member p65 and c-Rel as the key transcription factors for enhanced Foxp3 expression in Treg by gp96. Mutant gp96 within its Toll-like receptor (TLR) binding domain, TLR2 knockout (KO) mice, and mice with cell-specific deletion of MyD88, were used to demonstrate that gp96 activated Tregs and induced Foxp3 expression via a TLR2-MyD88-mediated NF-κB signaling pathway. Taken together, these results show that gp96 immunization restricted antibody- and Th-induced autoimmune diseases by integrating Treg expansion and activation, indicating its potential clinical usefulness against autoimmune diseases.