| First Author | Klose CS | Year | 2013 |
| Journal | Nature | Volume | 494 |
| Issue | 7436 | Pages | 261-5 |
| PubMed ID | 23334414 | Mgi Jnum | J:194555 |
| Mgi Id | MGI:5474158 | Doi | 10.1038/nature11813 |
| Citation | Klose CS, et al. (2013) A T-bet gradient controls the fate and function of CCR6-RORgammat+ innate lymphoid cells. Nature 494(7436):261-5 |
| abstractText | 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 to potent antimicrobial immunity are poorly defined. Mucosal retinoic-acid-receptor-related orphan receptor-gammat-positive (RORgammat(+)) innate lymphoid cells (ILCs) are emerging as an important innate lymphocyte population required for immunity to intestinal infections. Various subsets of RORgammat(+) ILCs have been described 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(-)RORgammat(+) ILCs. Postnatally emerging CCR6(-)RORgammat(+) ILCs upregulated T-bet and this was controlled by cues from the commensal microbiota and interleukin-23 (IL-23). In contrast, CCR6(+)RORgammat(+) 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(-)RORgammat(+) ILCs, but they could not differentiate into NKp46-expressing RORgammat(+) ILCs (that is, IL-22-producing natural killer (NK-22) cells) and failed to produce IFN-gamma. The production of IFN-gamma by T-bet-expressing CCR6(-)RORgammat(+) ILCs was essential for the release of mucus-forming glycoproteins required to protect the epithelial barrier during Salmonella enterica infection. Salmonella infection also causes severe enterocolitis that is at least partly driven by IFN-gamma. Mice deficient for T-bet or depleted of ILCs developed only mild enterocolitis. Thus, graded expression of T-bet in CCR6(-)RORgammat(+) ILCs facilitates the differentiation of IFN-gamma-producing CCR6(-)RORgammat(+) ILCs required to protect the epithelial barrier against Salmonella infections. Co-expression of T-bet and RORgammat, which is also found in subsets of IL-17-producing T-helper (T(H)17) cells, 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. |
