Abstract: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-γt-positive (RORγt(+)) innate lym… Show more
“…However, the overall number of Rorγt + ILC3 was similar suggesting that loss of NKp46 did not adversely affect the development of total ILC3 at steady-state. Nevertheless, analyses of T-bet expression revealed that it was upregulated within the NCR + subset in C57BL/6 mice as previously reported, 25,26 while NCR − ILC3 from Ly5.1 C14R mice did not show elevated levels of T-bet when compared with the NCR − population in C57BL/6 mice suggesting that NCR + cells fail to develop (Figure 3C). 10.1080/2162402X.2018.1475875-F0003Figure 3.Ly5.1 C14R mice have abnormal numbers of ILC3.…”
Section: Resultssupporting
confidence: 83%
“…NKp46 is also a key marker of one of the three subsets of ILC3. 18 In Ly5.1 C14R mice, as expected NCR + ILC3 were not detectable via NKp46 expression but we also did not see enrichment of expression of T-bet which is normally associated with induction of this subset, 25,26 although ILC3 development itself was not affected implying that activation of NKp46 is important for the transcriptional program of these cells. This is supported by cell fate mapping experiments that suggest that instability of NKp46 expression in ILC3s found in the intestine reflects a major role of this receptor in tuning the very dynamic environmental signals encountered that drive ILC3 plasticity.…”
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.
“…However, the overall number of Rorγt + ILC3 was similar suggesting that loss of NKp46 did not adversely affect the development of total ILC3 at steady-state. Nevertheless, analyses of T-bet expression revealed that it was upregulated within the NCR + subset in C57BL/6 mice as previously reported, 25,26 while NCR − ILC3 from Ly5.1 C14R mice did not show elevated levels of T-bet when compared with the NCR − population in C57BL/6 mice suggesting that NCR + cells fail to develop (Figure 3C). 10.1080/2162402X.2018.1475875-F0003Figure 3.Ly5.1 C14R mice have abnormal numbers of ILC3.…”
Section: Resultssupporting
confidence: 83%
“…NKp46 is also a key marker of one of the three subsets of ILC3. 18 In Ly5.1 C14R mice, as expected NCR + ILC3 were not detectable via NKp46 expression but we also did not see enrichment of expression of T-bet which is normally associated with induction of this subset, 25,26 although ILC3 development itself was not affected implying that activation of NKp46 is important for the transcriptional program of these cells. This is supported by cell fate mapping experiments that suggest that instability of NKp46 expression in ILC3s found in the intestine reflects a major role of this receptor in tuning the very dynamic environmental signals encountered that drive ILC3 plasticity.…”
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.
“…Furthermore, ILC1s accumulate in the inflamed intestine of CD patients 30. There also seems to be some plasticity between ILC1 and ILC3 cells 32, 33. Thus, ILCs secreting both IFN γ and IL‐17 in response to IL‐23, or IFN γ and IL‐22 in response to IL‐12+IL‐18 have been reported 26, 34.…”
Section: The Ilc Familymentioning
confidence: 99%
“…ILC1 cells are important anti‐bacterial cells, involved for example in the protection against Salmonella enterica 32. Furthermore, ILC1s accumulate in the inflamed intestine of CD patients 30.…”
SummaryNew data in the worlds of both innate‐like CD8+ T‐cells and natural killer (NK) cells have, in parallel, clarified some of the phenotypes of these cells and also their associated functions. While these cells are typically viewed entirely separately, the emerging innate functions of T‐cells and, similarly, the adaptive functions of NK cells suggest that many behaviours can be considered in parallel. In this review we compare the innate functions of CD8+ T‐cells (especially mucosal‐associated invariant T‐cells) and those of NK cells, and how these relate to expression of phenotypic markers, especially CD161 and CD56.
“…2). NKp46 + ILC3 are characterized by subset‐restricted expression of multiple genes required for their development and maturation, such as Il12rb2 , Tbx21 and Notch1 ,51, 61 and are defined by expression of eponymous NK cell‐associated receptors. Recent evidence suggests that NKp46 expression may act as a novel pattern recognition molecule to facilitate responses to fungal pathogens,62 whereas engagement of NKp44 on human ILC3 results in pro‐inflammatory cytokine production 63.…”
Section: Ilc3 Plasticity and Heterogeneitymentioning
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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