title: TCF-1 controls ILC2 and NKp46+RORγt+ innate lymphocyte differentiation and protection in intestinal inflammation.
abstract: Innate lymphocyte populations play a central role in conferring protective immunity at the mucosal frontier. In this study, we demonstrate that T cell factor 1 (TCF-1; encoded by Tcf7), a transcription factor also important for NK and T cell differentiation, is expressed by multiple innate lymphoid cell (ILC) subsets, including GATA3(+) nuocytes (ILC2) and NKp46(+) ILCs (ILC3), which confer protection against lung and intestinal inflammation. TCF-1 was intrinsically required for the differentiation of both ILC2 and NKp46(+) ILC3. Loss of TCF-1 expression impaired the capacity of these ILC subsets to produce IL-5, IL-13, and IL-22 and resulted in crippled responses to intestinal infection with Citrobacter rodentium. Furthermore, a reduction in T-bet expression required for Notch-2-dependent development of NKp46(+) ILC3 showed a dose-dependent reduction in TCF-1 expression. Collectively, our findings demonstrate an essential requirement for TCF-1 in ILC2 differentiation and reveal a link among Tcf7, Notch, and Tbx21 in NKp46(+) ILC3 development.
authors.affiliation: Division of Molecular Immunology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia;
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Mielke
authors.forename: Joanna R
authors.initials: JR
authors.lastname: Groom
authors.forename: Lucille C
authors.initials: LC
authors.lastname: Rankin
authors.forename: Cyril
authors.initials: C
authors.lastname: Seillet
authors.forename: Frederick
authors.initials: F
authors.lastname: Masson
authors.forename: Tracy
authors.initials: T
authors.lastname: Putoczki
authors.forename: Gabrielle T
authors.initials: GT
authors.lastname: Belz
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D044082:Citrobacter rodentium / Q000276:immunology; D004756:Enterobacteriaceae Infections / Q000276:immunology; D050990:GATA3 Transcription Factor / Q000378:metabolism; D051538:Hepatocyte Nuclear Factor 1-alpha; D007249:Inflammation / Q000276:immunology / Q000382:microbiology; D018793:Interleukin-13 / Q000096:biosynthesis; D015848:Interleukin-5 / Q000096:biosynthesis; D007378:Interleukins / Q000096:biosynthesis; D007422:Intestines / Q000276:immunology* / Q000382:microbiology; D007694:Killer Cells, Natural / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D009092:Mucous Membrane / Q000166:cytology / Q000276:immunology; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000378:metabolism; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism; D051883:Receptor, Notch2 / Q000378:metabolism; D051822:T Cell Transcription Factor 1 / Q000235:genetics / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000276:immunology; D013601:T-Lymphocytes / Q000378:metabolism*; D000097043:Interleukin-22; D000098815:T-bet Transcription Factor
chemical_list: D000950:Antigens, Ly; D050990:GATA3 Transcription Factor; D051538:Hepatocyte Nuclear Factor 1-alpha; D018793:Interleukin-13; D015848:Interleukin-5; D007378:Interleukins; D055627:Natural Cytotoxicity Triggering Receptor 1; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D051883:Receptor, Notch2; D051822:T Cell Transcription Factor 1; D020825:T-Box Domain Proteins; D000097043:Interleukin-22; D000098815:T-bet Transcription Factor; C494748:Gata3 protein, mouse; C496488:Hnf1a protein, mouse; C118384:Ncr1 protein, mouse; C497765:Notch2 protein, mouse