Induction of Foxp3 and activation of Tregs by HSP gp96 for treatment of autoimmune diseases
Yuxiu Xu,
Erlong Liu,
Xialin Xie,
Jiuru Wang,
Huaguo Zheng,
Ying Ju,
Lizhao Chen,
Changfei Li,
Xuyu Zhou,
Zihai Li,
Xin Li,
Songdong Meng
Affiliations
Yuxiu Xu
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Center for Biosafety Mega-Science, Chinese Academy of Sciences (CAS), No. 1 West Beichen Road, Chaoyang District, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing, P.R. China
Erlong Liu
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Center for Biosafety Mega-Science, Chinese Academy of Sciences (CAS), No. 1 West Beichen Road, Chaoyang District, Beijing 100101, China
Xialin Xie
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Center for Biosafety Mega-Science, Chinese Academy of Sciences (CAS), No. 1 West Beichen Road, Chaoyang District, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing, P.R. China
Jiuru Wang
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Center for Biosafety Mega-Science, Chinese Academy of Sciences (CAS), No. 1 West Beichen Road, Chaoyang District, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing, P.R. China
Huaguo Zheng
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Center for Biosafety Mega-Science, Chinese Academy of Sciences (CAS), No. 1 West Beichen Road, Chaoyang District, Beijing 100101, China
Ying Ju
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Center for Biosafety Mega-Science, Chinese Academy of Sciences (CAS), No. 1 West Beichen Road, Chaoyang District, Beijing 100101, China
Lizhao Chen
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Center for Biosafety Mega-Science, Chinese Academy of Sciences (CAS), No. 1 West Beichen Road, Chaoyang District, Beijing 100101, China
Changfei Li
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Center for Biosafety Mega-Science, Chinese Academy of Sciences (CAS), No. 1 West Beichen Road, Chaoyang District, Beijing 100101, China
Xuyu Zhou
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Center for Biosafety Mega-Science, Chinese Academy of Sciences (CAS), No. 1 West Beichen Road, Chaoyang District, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing, P.R. China
Zihai Li
Ohio State University, Columbus, OH, USA
Xin Li
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Center for Biosafety Mega-Science, Chinese Academy of Sciences (CAS), No. 1 West Beichen Road, Chaoyang District, Beijing 100101, China; Corresponding author
Songdong Meng
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Center for Biosafety Mega-Science, Chinese Academy of Sciences (CAS), No. 1 West Beichen Road, Chaoyang District, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing, P.R. China; Corresponding author
Summary: Upregulation and stabilization of Foxp3 expression in Tregs are essential for regulating Treg function and immune homeostasis. In this study, gp96 immunization showed obvious therapeutic effects in a Lyn–/– mouse model of systemic lupus erythematosus. Moreover, gp96 alleviated the initiation and progression of MOG-induced experimental autoimmune encephalomyelitis. Immunization of gp96 increased Treg frequency, expansion, and suppressive function. Gene expression profiling identified 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 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-induced and Th-induced autoimmune diseases by integrating Treg expansion and activation, indicating its potential clinical usefulness against autoimmune diseases.
