AT-bet gradient controls the fate and function of CCR6 ^sup -^ ROR[gamma]t^sup +^ innate lymphoid cells

• Published in: Nature (London) Vol. 494; no. 7436; p. 261
• 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 14.02.2013
• Subjects: Cytotoxicity; Genes; Glycoproteins; Immune system; Immunology; Infections; Lymphocytes
• ISSN: 0028-0836; 1476-4687

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 fromhomeostatic (often tissue-protective) function1 to potent antimicrobial immunity are poorly defined. Mucosal retinoic-acid-receptor-related orphan receptor-γt-positive (RORγt^sup +^) innate lymphoid cells (ILCs) are emerging as an important innate lymphocyte population required for immunity to intestinal infections2. Various subsets of RORγt^sup +^ ILCs have been described3-8 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^sup -^RORγt^sup +^ ILCs. Postnatally emerging CCR6^sup -^RORγt^sup +^ ILCs upregulated T-bet and this was controlled by cues from the commensal microbiota and interleukin-23 (IL-23). In contrast, CCR6^sup +^RORγt^sup +^ 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^sup -^RORγt^sup +^ ILCs, but they could not differentiate into NKp46-expressing RORγt^sup +^ 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^sup -^RORγt^sup +^ ILCs was essential for the release of mucus-forming glycoproteins required to protect the epithelial barrier during Salmonella enterica infection10,11. Salmonella infection also causes severe enterocolitis that is at least partly driven by IFN-γ12. Mice deficient for T-bet or depleted of ILCs developed only mild enterocolitis. Thus, graded expression of T-bet in CCR6^sup -^RORγt^sup +^ ILCs facilitates the differentiation of IFN-γ-producing CCR6^sup -^RORγt^sup +^ 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^sub H^17) cells13, 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. [PUBLICATION ABSTRACT]