title: Antigen-specific transforming growth factor β-induced Treg cells, but not natural Treg cells, ameliorate autoimmune arthritis in mice by shifting the Th17/Treg cell balance from Th17 predominance to Treg cell predominance.
abstract: OBJECTIVE
  Transferred CD4+CD25+FoxP3+ Treg cells can prevent autoimmune disease, but generally fail to ameliorate established disease. This study was undertaken to compare the effects of antigen-specific Treg cells induced with interleukin-2 (IL-2) and transforming growth factor β (TGFβ) ex vivo (induced Treg [iTreg] cells) to the effects of equivalent expanded thymus-derived natural Treg (nTreg) cells on established collagen-induced arthritis (CIA).
  
  
  METHODS
  CIA was induced in DBA/1 mice by immunization with type II collagen (CII), and before or shortly after immunization, mice were treated with iTreg or nTreg cells that were generated or expanded in vitro. Clinical scores were determined. Inflammatory responses were determined by measuring the levels of anti-CII antibody in the serum and examining the histologic features of the mouse joints. The Th1/Th17-mediated autoreactive response was evaluated by determining the cytokine profile of the draining lymph node (LN) cells of the mice by flow cytometry.
  
  
  RESULTS
  Following transfer, nTreg cells exhibited decreased FoxP3 and Bcl-2 expression and decreased suppressive activity, and many converted to Th17 cells. In contrast, transferred iTreg cells were more numerous, retained FoxP3 expression and their suppressive activity in the presence of IL-6, and were resistant to Th17 conversion. Notably, 10 days after the transfer of donor iTreg cells, predominance was shifted from Th17 cells to Treg cells in the draining LNs of recipient mice.
  
  
  CONCLUSIONS
  These findings provide evidence that transferred TGFβ-induced iTreg cells are more stable and functional than nTreg cells in mice with established autoimmunity. Moreover, iTreg cells can have tolerogenic effects even in the presence of ongoing inflammation. The therapeutic potential of human iTreg cells in subjects with chronic, immune-mediated inflammatory diseases should be investigated.
authors.affiliation: University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Kong
authors.forename: Qin
authors.initials: Q
authors.lastname: Lan
authors.forename: Maogen
authors.initials: M
authors.lastname: Chen
authors.forename: Julie
authors.initials: J
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.forename: David A
authors.initials: DA
authors.lastname: Horwitz
authors.forename: Valerie
authors.initials: V
authors.lastname: Quesniaux
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.forename: Zhongmin
authors.initials: Z
authors.lastname: Liu
authors.forename: David
authors.initials: D
authors.lastname: Brand
authors.forename: Hejian
authors.initials: H
authors.lastname: Zou
authors.forename: Song Guo
authors.initials: SG
authors.lastname: Zheng
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001327:Autoimmune Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism / Q000473:pathology*; D058504:Th17 Cells / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D016212:Transforming Growth Factor beta