title: CD4(+)Foxp3(+) Tregs protect against innate immune cell-mediated fulminant hepatitis in mice.
abstract: Foxp3(+) Tregs play important roles in maintaining homeostasis by suppressing excessive immune responses that result in serious tissue damage; yet, it is largely unknown about the impact of Tregs on innate immune cells in hepatitis models in vivo. In this study, we examined the effect of hepatic Tregs on innate immune-mediated liver injury by using the murine model of polyI:C and d-galactosamine (d-GalN)-induced hepatitis. Administration of polyI:C/d-GalN increased the number of CD4(+)Foxp3(+) Tregs in the liver. Depletion of Tregs leaded to higher levels of proinflammatory cytokine expression and severer liver injury, whereas adoptive transfer of Foxp3(+) Tregs attenuated liver injury in polyI:C/d-GalN-treated mice. In addition, depletion of Tregs leaded to a reduction in TGF-β and IL-10 expression in polyI:C/d-GalN-treated mice. Both of these cytokines were important for suppression of polyI:C/d-GalN-induced liver injury. TGF-β was derived from Tregs. IL-10 was derived from active Kupffer cells, and coincubation of Kupffer cells with Tregs increased IL-10 secretion. Furthermore, TGF-β blockade abrogated Treg-mediated suppression of proinflammatory cytokine production by innate immune cell in vitro.
  
  
  CONCLUSIONS
  CD4(+)Foxp3(+) Tregs modify innate immune responses in polyI:C/d-GalN-induced fulminant hepatitis via producing TGF-β and enhancing IL-10 secretion by Kupffer cells.
authors.affiliation: Department of Microbiology and Parasitology, Anhui Provincial Laboratory of Microbiology and Parasitology, Anhui Medical University, PR China. Electronic address: houxin45@mail.ustc.edu.cn.
authors.forename: Xin
authors.initials: X
authors.lastname: Hou
authors.affiliation: Department of Microbiology and Parasitology, Anhui Provincial Laboratory of Microbiology and Parasitology, Anhui Medical University, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Song
authors.affiliation: School of Life Sciences, Anhui Medical University, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Su
authors.affiliation: Integrated Laboratory of Anhui Medical University, PR China.
authors.forename: Dake
authors.initials: D
authors.lastname: Huang
authors.affiliation: Antagen Institute for Biomedical Research, Boston, MA, USA.
authors.forename: Wenda
authors.initials: W
authors.lastname: Gao
authors.affiliation: State Key laboratory of Trauma, Burns and Combined Injury, Department 1, Institute of Surgery Research, Daping Hospital, Third Military Medical University, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Microbiology and Parasitology, Anhui Provincial Laboratory of Microbiology and Parasitology, Anhui Medical University, PR China. Electronic address: shenjijia@hotmail.com.
authors.forename: Jijia
authors.initials: J
authors.lastname: Shen
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005688:Galactosamine / Q000008:administration & dosage; D006505:Hepatitis / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D007113:Immunity, Innate / Q000187:drug effects; D007267:Injections; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008212:Lymphocyte Depletion; D008297:Male; D008810:Mice, Inbred C57BL; D011070:Poly I-C / Q000008:administration & dosage / Q000494:pharmacology; D020011:Protective Agents / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D015704:CD4 Antigens; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D020011:Protective Agents; D005688:Galactosamine; D011070:Poly I-C
keywords: IL-10; Innate immune; Liver injury; TGF-β; Treg