A T-bet gradient controls the fate and function of CCR6−RORγt+ innate lymphoid cells

• Published in: Nature (London) Vol. 494; no. 7436; pp. 261 - 265
• Main Authors: Klose, Christoph S. N., Kiss, Elina A., Schwierzeck, Vera, Ebert, Karolina, Hoyler, Thomas, d’Hargues, Yannick, Göppert, Nathalie, Croxford, Andrew L., Waisman, Ari, Tanriver, Yakup, Diefenbach, Andreas
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.02.2013
• Subjects: 631/250/262; Animals; Antigens, Ly - genetics; Cell Differentiation; Cell Lineage; Cells, Cultured; Enterocolitis - immunology; Enterocolitis - metabolism; Enterocolitis - pathology; Epithelium - immunology; Epithelium - metabolism; Epithelium - microbiology; Humanities and Social Sciences; Immunity, Innate - immunology; Interferon-gamma - biosynthesis; Interferon-gamma - genetics; Interferon-gamma - immunology; Interleukin-23 - immunology; Intestinal Mucosa - cytology; Intestinal Mucosa - immunology; Intestinal Mucosa - microbiology; letter; Lymphocytes - cytology; Lymphocytes - immunology; Lymphocytes - metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mucus - secretion; multidisciplinary; Natural Cytotoxicity Triggering Receptor 1 - genetics; Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism; Receptors, CCR6 - deficiency; Receptors, CCR6 - metabolism; Salmonella Infections - immunology; Salmonella Infections - metabolism; Salmonella typhimurium - immunology; Salmonella typhimurium - pathogenicity; Science; T-Box Domain Proteins - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature11813

The graded expression of the transcription factor T-bet in CCR6 − RORγt + innate lymphoid cells is found to be involved in the control of interferon-γ expression, a cytokine that is required to protect the epithelial barrier against Salmonella infections. T-bet protein role in intestinal immunity The mechanisms by which immune cells switch from their routine tissue-protective mode to potent antimicrobial activity are poorly defined. This study shows that co-expression of the transcription factor T-bet and the nuclear receptor RORγt is required for the production of interferon gamma by the innate lymphoid cells in the lamina propria of the small intestine that provide epithelial protection against Salmonella infection in mice. 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 1 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 2 . Various subsets of RORγt + ILCs have been described 3 , 4 , 5 , 6 , 7 , 8 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) 3 , 9 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 10 , 11 . Salmonella infection also causes severe enterocolitis that is at least partly driven by IFN-γ 12 . 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 13 , 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.