A T-bet gradient controls the fate and function of CCR6(-)ROR gamma t(+) innate lymphoid cells

作者：Klose, Christoph S. N.; Kiss, Elina A.; Schwierzeck, Vera; Ebert, Karolina; Hoyler, Thomas; d'Hargues, Yannick; Goeppert, Nathalie; Croxford, Andrew L.; Waisman, Ari; Tanriver, Yakup; Diefenbach, Andreas^*

来源：Nature, 2013, 494(7436): 261-265.

DOI：10.1038/nature11813

• ROR-GAMMA-T
• NKP46(+) CELLS
• IFN-GAMMA
• EXPRESSION
• DIFFERENTIATION
• DEFENSE
• HOST

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) 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.

• 出版日期2013-2-14