title: The transcriptional regulators IRF4, BATF and IL-33 orchestrate development and maintenance of adipose tissue-resident regulatory T cells.
abstract: Foxp3(+) regulatory T (Treg) cells in visceral adipose tissue (VAT-Treg cells) are functionally specialized tissue-resident cells that prevent obesity-associated inflammation and preserve insulin sensitivity and glucose tolerance. Their development depends on the transcription factor PPAR-γ; however, the environmental cues required for their differentiation are unknown. Here we show that interleukin 33 (IL-33) signaling through the IL-33 receptor ST2 and myeloid differentiation factor MyD88 is essential for development and maintenance of VAT-Treg cells and sustains their transcriptional signature. Furthermore, the transcriptional regulators BATF and IRF4 were necessary for VAT-Treg differentiation through direct regulation of ST2 and PPAR-γ expression. IL-33 administration induced vigorous population expansion of VAT-Treg cells, which tightly correlated with improvements in metabolic parameters in obese mice. Human omental adipose tissue Treg cells also showed high ST2 expression, suggesting an evolutionarily conserved requirement for IL-33 in VAT-Treg cell homeostasis.
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] The Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Ajithkumar
authors.initials: A
authors.lastname: Vasanthakumar
authors.affiliation: 1] Laboratory for Immune Cell Systems, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. [2] Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Tokyo, Japan. [3] Division of Immunobiology, Department of Medical Life Science, Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan.
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Moro
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] The Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Annie
authors.initials: A
authors.lastname: Xin
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] The Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liao
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] The Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Renee
authors.initials: R
authors.lastname: Gloury
authors.affiliation: Laboratory for Mucosal Immunity, RIKEN Research Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Shimpei
authors.initials: S
authors.lastname: Kawamoto
authors.affiliation: Laboratory for Mucosal Immunity, RIKEN Research Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Sidonia
authors.initials: S
authors.lastname: Fagarasan
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] The Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Mielke
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] The Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Shoukat
authors.initials: S
authors.lastname: Afshar-Sterle
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] The Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Seth L
authors.identifier: 000000034763576X
authors.initials: SL
authors.lastname: Masters
authors.affiliation: 1] Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Tokyo, Japan. [2] Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Nakae
authors.affiliation: Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Saito
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] The Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: John M
authors.initials: JM
authors.lastname: Wentworth
authors.affiliation: Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Liao
authors.affiliation: Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Leonard
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] The Department of Mathematics and Statistics, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Smyth
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] Department of Computing and Information Systems, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] The Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Nutt
authors.affiliation: 1] Laboratory for Immune Cell Systems, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. [2] Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Koyasu
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] The Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Axel
authors.initials: A
authors.lastname: Kallies
mesh_terms: D000273:Adipose Tissue / Q000166:cytology* / Q000378:metabolism; D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D006801:Humans; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D000067596:Interleukin-33; D007378:Interleukins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009765:Obesity / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000378:metabolism; D000099218:Interferon Regulatory Factor-4
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D050835:Interferon Regulatory Factors; D000067596:Interleukin-33; D007378:Interleukins; D053594:Myeloid Differentiation Factor 88; D047495:PPAR gamma; D011956:Receptors, Cell Surface; D000099218:Interferon Regulatory Factor-4; C099359:BATF protein, human; C431772:Batf protein, mouse; C506536:IL33 protein, human; C506535:Il33 protein, mouse