title: Regulation of Effector Treg Cells in Murine Lupus.
abstract: Treg cells need to acquire an effector phenotype to function in settings of inflammation. Whether effector Treg cells can limit disease severity in lupus is unknown. Interferon regulatory factor 4 (IRF-4) is an essential controller of effector Treg cells and regulates their ability to express interleukin-10 (IL-10). In non-Treg cells, IRF-4 activity is modulated by interactions with DEF-6 and its homolog switch-associated protein 70 (SWAP-70). Although mice lacking both DEF-6 and SWAP-70 (double-knockout [DKO] mice) develop lupus, they display normal survival, suggesting that in DKO mice, Treg cells can moderate disease development. The purpose of this study was to investigate whether Treg cells from DKO mice have an increased capacity to become effector Treg cells due to the ability of DEF-6 and SWAP-70 to restrain IRF-4 activity.
  
  
  
  Treg cells were evaluated by fluorescence-activated cell sorting. The B lymphocyte-induced maturation protein 1 (BLIMP-1)/IL-10 axis was assessed by crossing DKO mice with BLIMP-1-YFP-10BiT dual-reporter mice. Deletion of IRF-4 in Treg cells from DKO mice was achieved by generating FoxP3(Cre) IRF-4(fl/fl) DKO mice.
  
  
  
  The concomitant absence of DEF-6 and SWAP-70 led to increased numbers of Treg cells, which acquired an effector phenotype in a cell-intrinsic manner. In addition, Treg cells from DKO mice exhibited enhanced expression of the BLIMP-1/IL-10 axis. Notably, DKO effector Treg cells survived and expanded as disease progressed. The accumulation of Treg cells from DKO mice was associated with the up-regulation of genes controlling autophagy. IRF-4 was required for the expansion and function of effector Treg cells from DKO mice.
  
  
  
  This study revealed the existence of mechanisms that, by acting on IRF-4, can fine-tune the function and survival of effector Treg cells in lupus. These findings suggest that the existence of a powerful effector Treg cell compartment that successfully survives in an unfavorable inflammatory environment could limit disease development.
authors.affiliation: Hospital for Special Surgery, New York, New York.
authors.forename: Uma
authors.initials: U
authors.lastname: Chandrasekaran
authors.affiliation: Hospital for Special Surgery, New York, New York.
authors.forename: Woelsung
authors.initials: W
authors.lastname: Yi
authors.affiliation: Hospital for Special Surgery, New York, New York.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Hospital for Special Surgery and Weill Cornell Graduate School of Medical Sciences, New York, New York.
authors.forename: Chien-Huan
authors.initials: CH
authors.lastname: Weng
authors.affiliation: Hospital for Special Surgery, New York, and New York City College of Technology, City University of New York, Brooklyn, New York.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Giannopoulou
authors.affiliation: Hospital for Special Surgery, New York, New York.
authors.forename: Yurii
authors.initials: Y
authors.lastname: Chinenov
authors.affiliation: Dresden University of Technology, Dresden, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Jessberger
authors.affiliation: University of Alabama at Birmingham.
authors.forename: Casey T
authors.initials: CT
authors.lastname: Weaver
authors.affiliation: Columbia University Medical Center and New York Presbyterian Hospital, New York, New York.
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
authors.affiliation: Hospital for Special Surgery, Weill Cornell Graduate School of Medical Sciences, and Weill Cornell Medicine, Cornell University, New York, New York.
authors.forename: Alessandra B
authors.initials: AB
authors.lastname: Pernis
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000096:biosynthesis; D050835:Interferon Regulatory Factors / Q000502:physiology*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens / Q000096:biosynthesis; D009687:Nuclear Proteins / Q000096:biosynthesis; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism / Q000502:physiology*; D000099218:Interferon Regulatory Factor-4
chemical_list: D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D050835:Interferon Regulatory Factors; D015778:Minor Histocompatibility Antigens; D009687:Nuclear Proteins; D000099218:Interferon Regulatory Factor-4; C473249:Def6 protein, mouse; C113365:Swap70 protein, mouse
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