title: A network of high-mobility group box transcription factors programs innate interleukin-17 production.
abstract: How innate lymphoid cells (ILCs) in the thymus and gut become specialized effectors is unclear. The prototypic innate-like γδ T cells (Tγδ17) are a major source of interleukin-17 (IL-17). We demonstrate that Tγδ17 cells are programmed by a gene regulatory network consisting of a quartet of high-mobility group (HMG) box transcription factors, SOX4, SOX13, TCF1, and LEF1, and not by conventional TCR signaling. SOX4 and SOX13 directly regulated the two requisite Tγδ17 cell-specific genes, Rorc and Blk, whereas TCF1 and LEF1 countered the SOX proteins and induced genes of alternate effector subsets. The T cell lineage specification factor TCF1 was also indispensable for the generation of IL-22 producing gut NKp46(+) ILCs and restrained cytokine production by lymphoid tissue inducer-like effectors. These results indicate that similar gene network architecture programs innate sources of IL-17, independent of anatomical origins.
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Malhotra
authors.forename: Kavitha
authors.initials: K
authors.lastname: Narayan
authors.forename: Ok Hyun
authors.initials: OH
authors.lastname: Cho
authors.forename: Katelyn E
authors.initials: KE
authors.lastname: Sylvia
authors.forename: Catherine
authors.initials: C
authors.lastname: Yin
authors.forename: Heather
authors.initials: H
authors.lastname: Melichar
authors.forename: Mehdi
authors.initials: M
authors.lastname: Rashighi
authors.forename: Veronique
authors.initials: V
authors.lastname: Lefebvre
authors.forename: John E
authors.initials: JE
authors.lastname: Harris
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Berg
authors.forename: Joonsoo
authors.initials: J
authors.lastname: Kang
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D053263:Gene Regulatory Networks / Q000276:immunology; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism*; D007113:Immunity, Innate / Q000235:genetics; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000235:genetics; D007378:Interleukins / Q000276:immunology; D007422:Intestines / Q000276:immunology*; D016131:Lymphocyte Subsets / Q000276:immunology*; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000378:metabolism; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D055751:SOXC Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D015533:Transcriptional Activation / Q000276:immunology; D000097043:Interleukin-22
chemical_list: D000950:Antigens, Ly; D001324:Autoantigens; D051538:Hepatocyte Nuclear Factor 1-alpha; D006609:High Mobility Group Proteins; D020381:Interleukin-17; D007378:Interleukins; D051821:Lymphoid Enhancer-Binding Factor 1; D055627:Natural Cytotoxicity Triggering Receptor 1; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D016692:Receptors, Antigen, T-Cell, gamma-delta; D055751:SOXC Transcription Factors; D000097043:Interleukin-22; C496488:Hnf1a protein, mouse; C497574:Lef1 protein, mouse; C118384:Ncr1 protein, mouse; C110455:Sox13 protein, mouse; C489990:Sox4 protein, mouse
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