title: A T-bet gradient controls the fate and function of CCR6-RORγt+ innate lymphoid cells.
abstract: At mucosal surfaces, the immune system should not initiate inflammatory immune responses to the plethora of antigens constantly present in the environment, but should remain poised to unleash a potent assault on intestinal pathogens. The transcriptional programs and regulatory factors required for immune cells to switch from homeostatic (often tissue-protective) function to potent antimicrobial immunity are poorly defined. Mucosal retinoic-acid-receptor-related orphan receptor-γt-positive (RORγt(+)) innate lymphoid cells (ILCs) are emerging as an important innate lymphocyte population required for immunity to intestinal infections. Various subsets of RORγt(+) ILCs have been described but the transcriptional programs controlling their specification and fate remain largely unknown. Here we provide evidence that the transcription factor T-bet determines the fate of a distinct lineage of CCR6(-)RORγt(+) ILCs. Postnatally emerging CCR6(-)RORγt(+) ILCs upregulated T-bet and this was controlled by cues from the commensal microbiota and interleukin-23 (IL-23). In contrast, CCR6(+)RORγt(+) ILCs, which arise earlier during ontogeny, did not express T-bet. T-bet instructed the expression of T-bet target genes such as interferon-γ (IFN-γ) and of the natural cytotoxicity receptor NKp46. Mice genetically lacking T-bet showed normal development of CCR6(-)RORγt(+) ILCs, but they could not differentiate into NKp46-expressing RORγt(+) ILCs (that is, IL-22-producing natural killer (NK-22) cells) and failed to produce IFN-γ. The production of IFN-γ by T-bet-expressing CCR6(-)RORγt(+) ILCs was essential for the release of mucus-forming glycoproteins required to protect the epithelial barrier during Salmonella enterica infection. Salmonella infection also causes severe enterocolitis that is at least partly driven by IFN-γ. Mice deficient for T-bet or depleted of ILCs developed only mild enterocolitis. Thus, graded expression of T-bet in CCR6(-)RORγt(+) ILCs facilitates the differentiation of IFN-γ-producing CCR6(-)RORγt(+) ILCs required to protect the epithelial barrier against Salmonella infections. Co-expression of T-bet and RORγt, which is also found in subsets of IL-17-producing T-helper (T(H)17) cells, may be an evolutionarily conserved transcriptional program that originally developed as part of the innate defence against infections but that also confers an increased risk of immune-mediated pathology.
authors: Institute of Medical Microbiology and Hygiene, University of Freiburg, Hermann-Herder-Strasse 11, D-79104 Freiburg, Germany.
authors: Christoph S N
authors: CS
authors: Klose
authors: Elina A
authors: EA
authors: Kiss
authors: Vera
authors: V
authors: Schwierzeck
authors: Karolina
authors: K
authors: Ebert
authors: Thomas
authors: T
authors: Hoyler
authors: Yannick
authors: Y
authors: d'Hargues
authors: Nathalie
authors: N
authors: Göppert
authors: Andrew L
authors: AL
authors: Croxford
authors: Ari
authors: A
authors: Waisman
authors: Yakup
authors: Y
authors: Tanriver
authors: Andreas
authors: A
authors: Diefenbach
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000235:genetics; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D004760:Enterocolitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004848:Epithelium / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D007113:Immunity, Innate / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D053759:Interleukin-23 / Q000276:immunology; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology / Q000382:microbiology; D008214:Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009093:Mucus / Q000378:metabolism; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000235:genetics; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism*; D054399:Receptors, CCR6 / Q000172:deficiency* / Q000378:metabolism; D012480:Salmonella Infections / Q000276:immunology / Q000378:metabolism; D012486:Salmonella typhimurium / Q000276:immunology / Q000472:pathogenicity; D020825:T-Box Domain Proteins / Q000378:metabolism*; D000098815:T-bet Transcription Factor
chemical_list: D000950:Antigens, Ly; C498126:CCR6 protein, mouse; D053759:Interleukin-23; D055627:Natural Cytotoxicity Triggering Receptor 1; C118384:Ncr1 protein, mouse; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D054399:Receptors, CCR6; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma