RORγt and commensal microflora are required for the differentiation of mucosal interleukin 22–producing NKp46+ cells

Sanos, Stéphanie L.; Bui, Viet L.; Mortha, Arthur; Oberle, Karin; Heners, Charlotte; Johner, Caroline; Diefenbach, Andreas

doi:10.1038/ni.1684

Cited by 780 publications

(931 citation statements)

References 45 publications

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“…Aldara-induced IL-17 seems not crucial for the phenotype observed after 24 h, because RORc-ko mice, which lack the transcription factor RORgt and are therefore impaired in IL-17 and IL-22 production 24,35,36 , displayed acanthosis, epidermal hyperproliferation and scaling to a similar extent as in C57BL/6 controls ( Supplementary Fig. S8).…”

Section: Article Nature Communications | Doi: 101038/ncomms2566mentioning

confidence: 98%

Aldara activates TLR7-independent immune defence

et al. 2013

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Aldara is a cream used for topical treatment of non-melanoma skin cancer, and is thought to act through stimulation of anti-tumour immunity. The active ingredient, imiquimod, has been shown to stimulate toll-like receptor 7. Aldara also induces psoriasis-like lesions when applied to naive murine skin, and as such is used as a mouse model for psoriasis. Here we find that in naive murine skin, Aldara induces inflammation largely independently of toll-like receptor 7. Surprisingly, inflammasome activation, keratinocyte death and interleukin 1 release also occur in response to the vehicle cream in the absence of imiquimod. We show that isostearic acid, a major component of the vehicle, promotes inflammasome activation in cultured keratinocytes, and so may contribute to the observed effects of Aldara on murine skin. Aldara therefore stimulates at least two immune pathways independently, and both imiquimod and vehicle are required for a full inflammatory response. Although it remains to be tested, it is possible that imiquimod-independent effects also contribute to the therapeutic efficacy of Aldara.

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Section: Article Nature Communications | Doi: 101038/ncomms2566mentioning

confidence: 98%

Aldara activates TLR7-independent immune defence

et al. 2013

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“…Expression of ROR γ t is essential for the development and maturation of all members of the ILC3 family, including fetal LTi, adult LTi‐like ILC3 and NKp46 + ILC3 24, 25, 26, 27. ROR γ t‐expressing progenitors are present in the fetal liver of mice 14.…”

Section: Group 3 Innate Lymphoid Cell Developmentmentioning

confidence: 99%

Functional and phenotypic heterogeneity of group 3 innate lymphoid cells

2017

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SummaryGroup 3 innate lymphoid cells (ILC3), defined by expression of the transcription factor retinoid‐related orphan receptor γt, play key roles in the regulation of inflammation and immunity in the gastrointestinal tract and associated lymphoid tissues. ILC3 consist largely of two major subsets, NCR + ILC3 and LTi‐like ILC3, but also demonstrate significant plasticity and heterogeneity. Recent advances have begun to dissect the relationship between ILC3 subsets and to define distinct functional states within the intestinal tissue microenvironment. In this review we discuss the ever‐expanding roles of ILC3 in the context of intestinal homeostasis, infection and inflammation – with a focus on comparing and contrasting the relative contributions of ILC3 subsets.

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“…3,4 NKp46 is expressed by NK cells and group 1 and 3 innate lymphoid cells (ILCs). 5-7 NKp46 is encoded by Ncr1 and associates with the ITAM-containing CD3ζ or FcRγ polypeptides. Several endogenous ligands of NKp46 have been described including the complement factor P, 8 the intracellular filamentous cytoskeletal protein vimentin expressed on the surface of Mycobacterium tuberculosis –infected monocytes, 9 and several viral proteins such as hemagglutinin and hemagglutinin neuraminidases of the influenza, 10,11 Sendai, 12 Newcastle disease, 13 ectromelia and vaccinia viruses.…”

Section: Introductionmentioning

confidence: 99%

A point mutation in the Ncr1 signal peptide impairs the development of innate lymphoid cell subsets

et al. 2018

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NKp46 (CD335) is a surface receptor shared by both human and mouse natural killer (NK) cells and innate lymphoid cells (ILCs) that transduces activating signals necessary to eliminate virus-infected cells and tumors. Here, we describe a spontaneous point mutation of cysteine to arginine (C14R) in the signal peptide of the NKp46 protein in congenic Ly5.1 mice and the newly generated NCRB6C14R strain. Ly5.1C14R NK cells expressed similar levels of Ncr1 mRNA as C57BL/6, but showed impaired surface NKp46 and reduced ability to control melanoma tumors in vivo. Expression of the mutant NKp46C14R in 293T cells showed that NKp46 protein trafficking to the cell surface was compromised. Although Ly5.1C14R mice had normal number of NK cells, they showed an increased number of early maturation stage NK cells. CD49a+ILC1s were also increased but these cells lacked the expression of TRAIL. ILC3s that expressed NKp46 were not detectable and were not apparent when examined by T-bet expression. Thus, the C14R mutation reveals that NKp46 is important for NK cell and ILC differentiation, maturation and function.SignificanceInnate lymphoid cells (ILCs) play important roles in immune protection. Various subsets of ILCs express the activating receptor NKp46 which is capable of recognizing pathogen derived and tumor ligands and is necessary for immune protection. Here, we describe a spontaneous point mutation in the signal peptide of the NKp46 protein in congenic Ly5.1 mice which are widely used for tracking cells in vivo. This Ncr1 C14R mutation impairs NKp46 surface expression resulting in destabilization of Ncr1 and accumulation of NKp46 in the endoplasmic reticulum. Loss of stable NKp46 expression impaired the maturation of NKp46+ ILCs and altered the expression of TRAIL and T-bet in ILC1 and ILC3, respectively.

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RORγt and commensal microflora are required for the differentiation of mucosal interleukin 22–producing NKp46+ cells

Cited by 780 publications

References 45 publications

Aldara activates TLR7-independent immune defence

Aldara activates TLR7-independent immune defence

Functional and phenotypic heterogeneity of group 3 innate lymphoid cells

A point mutation in the Ncr1 signal peptide impairs the development of innate lymphoid cell subsets

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