Journal
NATURE
Volume 494, Issue 7436, Pages 261-265Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature11813
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Funding
- Deutsche Forschungsgemeinschaft [SFB620/A14, TA436/2-1]
- German Federal Ministry of Education and Research [BMBF 01 EO 0803]
- EFSD/Lilly grant
- European Research Council
- CCI Walter-Hitzig-Fellowship
- EMBO Long Term Fellowship [ALTF 508-2011]
- FP6 Marie Curie Research Train in Network [MRTN-CT-2004-005632]
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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-acidreceptor-related orphan receptor-gamma t-positive (ROR gamma t(+)) innate lymphoid cells (ILCs) are emerging as an important innate lymphocyte population required for immunity to intestinal infections(2). Various subsets of ROR gamma t(+) ILCs have been described(3-8) 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(-)ROR gamma t(+) ILCs. Postnatally emerging CCR6(-)ROR gamma t(+) ILCs upregulated T-bet and this was controlled by cues from the commensal microbiota and interleukin-23 (IL-23). In contrast, CCR6(+)ROR gamma t(+) ILCs, which arise earlier during ontogeny, did not express T-bet. T-bet instructed the expression of T-bet target genes such as interferon-gamma (IFN-gamma) and of the natural cytotoxicity receptor NKp46. Mice genetically lacking T-bet showed normal development of CCR6(-)ROR gamma t(+) ILCs, but they could not differentiate into NKp46-expressing ROR gamma t(+) ILCs (that is, IL-22-producing natural killer (NK-22) cells)(3,9) and failed to produce IFN-gamma. The production of IFN-gamma by T-bet-expressing CCR6(-)ROR gamma t(+) 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-gamma(12). Mice deficient for T-bet or depleted of ILCs developed only mild enterocolitis. Thus, graded expression of T-bet in CCR6(-)ROR gamma t(+) MCs facilitates the differentiation of IFN-gamma-producing CCR6(-)ROR gamma t(+) ILCs required to protect the epithelial barrier against Salmonella infections. Co-expression of T-bet and ROR gamma t, 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.
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