title: Nfil3 is crucial for development of innate lymphoid cells and host protection against intestinal pathogens.
abstract: The bZIP transcription factor Nfil3 (also known as E4BP4) is required for the development of natural killer (NK) cells and type 1 innate lymphoid cells (ILC1s). We find that Nfil3 plays a critical role in the development of other mucosal tissue-associated innate lymphocytes. Type 3 ILCs (ILC3s), including lymphoid tissue inducer (LTi)-like cells, are severely diminished in both numbers and function in Nfil3-deficient mice. Using mixed bone marrow chimeric mice, we demonstrate that Nfil3 is critical for normal development of gut-associated ILC3s in a cell-intrinsic manner. Furthermore, Nfil3 deficiency severely compromises intestinal innate immune defense against acute bacterial infection with Citrobacter rodentium and Clostridium difficile. Nfil3 deficiency resulted in a loss of the recently identified ILC precursor, yet conditional ablation of Nfil3 in the NKp46(+) ILC3 subset did not perturb ILC3 numbers, suggesting that Nfil3 is required early during ILC3 development but not for lineage maintenance. Lastly, a marked defect in type 2 ILCs (ILC2s) was also observed in the lungs and visceral adipose tissue of Nfil3-deficient mice, revealing a general requirement for Nfil3 in the development of all ILC lineages.
authors.affiliation: Immunology Program; Adult Bone Marrow Transplant Service and Infectious Diseases Service, Department of Medicine; and Lucille Castori Center for Microbes, Inflammation, and Cancer, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Geiger
authors.affiliation: Immunology Program; Adult Bone Marrow Transplant Service and Infectious Diseases Service, Department of Medicine; and Lucille Castori Center for Microbes, Inflammation, and Cancer, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Abt
authors.affiliation: Immunology Program; Adult Bone Marrow Transplant Service and Infectious Diseases Service, Department of Medicine; and Lucille Castori Center for Microbes, Inflammation, and Cancer, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Georg
authors.initials: G
authors.lastname: Gasteiger
authors.affiliation: Immunology Program; Adult Bone Marrow Transplant Service and Infectious Diseases Service, Department of Medicine; and Lucille Castori Center for Microbes, Inflammation, and Cancer, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Firth
authors.affiliation: Immunology Program; Adult Bone Marrow Transplant Service and Infectious Diseases Service, Department of Medicine; and Lucille Castori Center for Microbes, Inflammation, and Cancer, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Margaret H
authors.initials: MH
authors.lastname: O'Connor
authors.affiliation: Immunology Program; Adult Bone Marrow Transplant Service and Infectious Diseases Service, Department of Medicine; and Lucille Castori Center for Microbes, Inflammation, and Cancer, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Clair D
authors.initials: CD
authors.lastname: Geary
authors.affiliation: Immunology Program; Adult Bone Marrow Transplant Service and Infectious Diseases Service, Department of Medicine; and Lucille Castori Center for Microbes, Inflammation, and Cancer, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Timothy E
authors.initials: TE
authors.lastname: O'Sullivan
authors.affiliation: Immunology Program; Adult Bone Marrow Transplant Service and Infectious Diseases Service, Department of Medicine; and Lucille Castori Center for Microbes, Inflammation, and Cancer, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 Immunology Program; Adult Bone Marrow Transplant Service and Infectious Diseases Service, Department of Medicine; and Lucille Castori Center for Microbes, Inflammation, and Cancer, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Marcel R
authors.initials: MR
authors.lastname: van den Brink
authors.affiliation: Immunology Program; Adult Bone Marrow Transplant Service and Infectious Diseases Service, Department of Medicine; and Lucille Castori Center for Microbes, Inflammation, and Cancer, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 Immunology Program; Adult Bone Marrow Transplant Service and Infectious Diseases Service, Department of Medicine; and Lucille Castori Center for Microbes, Inflammation, and Cancer, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 Immunology Program; Adult Bone Marrow Transplant Service and Infectious Diseases Service, Department of Medicine; and Lucille Castori Center for Microbes, Inflammation, and Cancer, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Eric G
authors.initials: EG
authors.lastname: Pamer
authors.affiliation: Immunology Program; Adult Bone Marrow Transplant Service and Infectious Diseases Service, Department of Medicine; and Lucille Castori Center for Microbes, Inflammation, and Cancer, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Hanash
authors.affiliation: Immunology Program; Adult Bone Marrow Transplant Service and Infectious Diseases Service, Department of Medicine; and Lucille Castori Center for Microbes, Inflammation, and Cancer, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY 10065 sunj@mskcc.org.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Sun
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000276:immunology; D050976:Basic-Leucine Zipper Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D044082:Citrobacter rodentium / Q000276:immunology / Q000472:pathogenicity; D016360:Clostridioides difficile / Q000276:immunology / Q000472:pathogenicity; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology*; D007113:Immunity, Innate / Q000235:genetics; D018928:Immunity, Mucosal / Q000235:genetics; D007422:Intestines / Q000276:immunology / Q000382:microbiology; D007694:Killer Cells, Natural / Q000276:immunology; D016131:Lymphocyte Subsets / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018183:Transplantation Chimera / Q000276:immunology
chemical_list: D000950:Antigens, Ly; D050976:Basic-Leucine Zipper Transcription Factors; D055627:Natural Cytotoxicity Triggering Receptor 1; C118384:Ncr1 protein, mouse; C497441:Nfil3 protein, mouse; D012333:RNA, Messenger
references.citation: Immunity. 2013 Sep 19;39(3):622-622.e1
references.pmid: 24012419
references.citation: J Exp Med. 2014 Feb 10;211(2):199-208
references.pmid: 24419270
references.citation: Immunity. 2012 Oct 19;37(4):649-59
references.pmid: 23063330
references.citation: Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2609-14
references.pmid: 9122243
references.citation: Nat Immunol. 2011 Nov 20;13(2):144-51
references.pmid: 22101730
references.citation: Nature. 2009 Feb 5;457(7230):722-5
references.pmid: 18978771
references.citation: Proc Natl Acad Sci U S A. 2013 Jun 18;110(25):10240-5
references.pmid: 23733962
references.citation: Nat Immunol. 2009 Jan;10(1):83-91
references.pmid: 19029903
references.citation: Science. 2010 Oct 29;330(6004):665-9
references.pmid: 20929731
references.citation: Cell. 2014 Apr 10;157(2):340-356
references.pmid: 24725403
references.citation: Mol Cell Biol. 1995 Nov;15(11):6055-63
references.pmid: 7565758
references.citation: Nature. 2013 Oct 10;502(7470):245-8
references.pmid: 24037376
references.citation: N Engl J Med. 2008 Oct 30;359(18):1932-40
references.pmid: 18971494
references.citation: Immunity. 2012 Sep 21;37(3):463-74
references.pmid: 22981535
references.citation: Nature. 2014 Apr 17;508(7496):397-401
references.pmid: 24509713
references.citation: Nat Immunol. 2011 Jan;12(1):21-7
references.pmid: 21113163
references.citation: Nature. 1999 Feb 25;397(6721):702-6
references.pmid: 10067894
references.citation: Nat Rev Immunol. 2013 Feb;13(2):75-87
references.pmid: 23292121
references.citation: Immunity. 2012 Jan 27;36(1):92-104
references.pmid: 22177117
references.citation: Proc Natl Acad Sci U S A. 2011 Nov 8;108(45):18324-9
references.pmid: 22021440
references.citation: Nat Rev Immunol. 2013 Feb;13(2):145-9
references.pmid: 23348417
references.citation: J Exp Med. 2014 Apr 7;211(4):635-42
references.pmid: 24663216
references.citation: J Exp Med. 2012 Jul 30;209(8):1445-56
references.pmid: 22826298
references.citation: J Exp Med. 2013 Mar 11;210(3):535-49
references.pmid: 23420878
references.citation: J Exp Med. 2013 Dec 16;210(13):2981-90
references.pmid: 24277151
references.citation: J Immunol. 2014 Feb 15;192(4):1918-27
references.pmid: 24442434
references.citation: J Immunol. 2011 Apr 15;186(8):4649-55
references.pmid: 21383239
references.citation: Proc Natl Acad Sci U S A. 2010 Jan 12;107(2):821-6
references.pmid: 20080759
references.citation: EMBO J. 2011 May 18;30(10):2071-82
references.pmid: 21499227
references.citation: Immunity. 2011 Jan 28;34(1):122-34
references.pmid: 21194981
references.citation: Science. 2012 Jun 8;336(6086):1321-5
references.pmid: 22674331
references.citation: Nat Immunol. 2013 Apr;14(4):389-95
references.pmid: 23455676
references.citation: Nat Immunol. 2011 May;12(5):450-9
references.pmid: 21460847
references.citation: J Immunol. 2013 Aug 15;191(4):1818-26
references.pmid: 23851685
references.citation: Nat Immunol. 2009 Jan;10(1):75-82
references.pmid: 19029904
references.citation: Immunity. 2012 Oct 19;37(4):634-48
references.pmid: 23063333
references.citation: Immunity. 2012 Aug 24;37(2):339-50
references.pmid: 22921121
references.citation: J Exp Med. 2009 Dec 21;206(13):2977-86
references.pmid: 19995955
references.citation: J Exp Med. 2010 Feb 15;207(2):273-80
references.pmid: 20142427
references.citation: Nat Immunol. 2011 Sep 11;12(10):949-58
references.pmid: 21909092
references.citation: Cell. 2011 May 27;145(5):745-57
references.pmid: 21565393
references.citation: J Immunol. 2011 Dec 1;187(11):5505-9
references.pmid: 22025549
references.citation: Nat Rev Microbiol. 2009 Jul;7(7):526-36
references.pmid: 19528959
references.citation: Annu Rev Immunol. 2012;30:647-75
references.pmid: 22224763
references.citation: Nat Immunol. 2009 Oct;10(10):1118-24
references.pmid: 19749763
references.citation: Nature. 2010 Jan 28;463(7280):540-4
references.pmid: 20023630
references.citation: Nat Immunol. 2011 Dec 04;13(1):58-66
references.pmid: 22138715
references.citation: Nat Immunol. 2012 Jan 22;13(3):229-36
references.pmid: 22267218
references.citation: Science. 2011 Dec 16;334(6062):1561-5
references.pmid: 22033518
references.citation: J Immunol. 2013 Oct 15;191(8):4383-91
references.pmid: 24038093
references.citation: Nature. 2008 May 1;453(7191):106-9
references.pmid: 18362914
references.citation: Science. 2013 Nov 8;342(6159):727-30
references.pmid: 24202171
references.citation: Nat Immunol. 2013 Dec;14(12):1229-36
references.pmid: 24141388
references.citation: Blood. 2011 Jun 9;117(23):6193-7
references.pmid: 21474667
references.citation: Nat Immunol. 2004 Jan;5(1):64-73
references.pmid: 14691482
references.citation: J Exp Med. 2012 Apr 9;209(4):729-40
references.pmid: 22430492
references.citation: Nature. 2013 Feb 14;494(7436):261-5
references.pmid: 23334414
references.citation: Immunity. 2013 Apr 18;38(4):694-704
references.pmid: 23601684
references.citation: Nature. 2009 Jan 29;457(7229):557-61
references.pmid: 19136945
references.citation: Immunity. 2013 Apr 18;38(4):769-81
references.pmid: 23453631
references.citation: Infect Immun. 2012 Jan;80(1):62-73
references.pmid: 22006564
references.citation: Immunity. 2008 Dec 19;29(6):958-70
references.pmid: 19084435
references.citation: Blood. 2011 Nov 17;118(20):5439-47
references.pmid: 21931117
references.citation: J Exp Med. 2012 Dec 17;209(13):2331-8
references.pmid: 23209316