title: Induction of regulatory T cells by high-dose gp96 suppresses murine liver immune hyperactivation.
abstract: Immunization with high-dose heat shock protein gp96, an endoplasmic reticulum counterpart of the Hsp90 family, significantly enhances regulatory T cell (Treg) frequency and suppressive function. Here, we examined the potential role and mechanism of gp96 in regulating immune-mediated hepatic injury in mice. High-dose gp96 immunization elicited rapid and long-lasting protection of mice against concanavalin A (Con A)-and anti-CD137-induced liver injury, as evidenced by decreased alanine aminotransaminase (ALT) levels, hepatic necrosis, serum pro-inflammatory cytokines (IFN-γ, TNF-α, and IL-6), and number of IFN-γ (+) CD4(+) and IFN-γ (+) CD8(+) T cells in the spleen and liver. In contrast, CD4(+)CD25(+)Foxp3(+) Treg frequency and suppressive function were both increased, and the protective effect of gp96 could be generated by adoptive transfer of Treg cells from gp96-immunized mice. In vitro co-culture experiments demonstrated that gp96 stimulation enhanced Treg proliferation and suppressive function, and up-regulation of Foxp3, IL-10, and TGF-β1 induced by gp96 was dependent on TLR2- and TLR4-mediated NF-κB activation. Our work shows that activation of Tregs by high-dose gp96 immunization protects against Con A- and anti-CD137-induced T cell-hepatitis and provides therapeutic potential for the development of a gp96-based anti-immune hyperactivation vaccine against immune-mediated liver destruction.
authors.affiliation: Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Xinghui
authors.initials: X
authors.lastname: Li
authors.forename: Zhen
authors.initials: Z
authors.lastname: Liu
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Yan
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Zhang
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Bao
authors.initials: B
authors.lastname: Zhao
authors.forename: Shengdian
authors.initials: S
authors.lastname: Wang
authors.forename: Xuyu
authors.initials: X
authors.lastname: Zhou
authors.forename: George F
authors.initials: GF
authors.lastname: Gao
authors.forename: Songdong
authors.initials: S
authors.lastname: Meng
mesh_terms: D019264:Adoptive Transfer; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology* / Q000473:pathology; D003208:Concanavalin A / Q000633:toxicity; D016207:Cytokines / Q000097:blood; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D007114:Immunization / Q000379:methods; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D051379:Mice; D013154:Spleen / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D016207:Cytokines; D008562:Membrane Glycoproteins; C053387:endoplasmin; D003208:Concanavalin A; D000410:Alanine Transaminase