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

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.