NK Cell Recognition of Candida glabrata through Binding of NKp46 and NCR1 to Fungal Ligands Epa1, Epa6, and Epa7

Vitenshtein, Alon; Charpak-Amikam, Yoav; Yamin, Rachel; Bauman, Yoav; Isaacson, Batya; Stein, Natan; Berhani, Orit; Dassa, Liat; Gamliel, Moriya; Gur, Chamutal; Glasner, Ariella; Gómez, Carlos M. Meléndez; Ben‐Ami, Ronen; Osherov, Nir; Cormack, Brendan P.; Mandelboim, Ofer

doi:10.1016/j.chom.2016.09.008

Cited by 78 publications

(87 citation statements)

References 37 publications

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“…14 NKp46 was also shown to recognize PfEMP1 of Plasmodium falciparum , 14 an unknown ligand from Fusobacterium nucleatum , 15 adhesins from Candida glabrata . 16 This wide expression supports that the triggering of NKp46 is essential for effective immune responses.…”

Section: Introductionmentioning

confidence: 68%

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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Section: Introductionmentioning

confidence: 68%

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

et al. 2018

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“…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. Although NCR + ILC3 are largely thought to be non‐cytotoxic cells, NKp46 + ILC3 express Gzmc – which encodes a murine granzyme molecule known to induce cell death 60, 64.…”

Section: Ilc3 Plasticity and Heterogeneitymentioning

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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“…NK cells participate in many immunological activities, from killing cancerous cells (1)(2)(3)(4)(5)(6)(7) and fighting bacteria (8-10) and fungi (11) to playing roles in allergy (12) and graft-versushost disease (13). NK cells also play roles in autoimmunity (14-18) and pregnancy (19).…”

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confidence: 99%

Zika Virus Escapes NK Cell Detection by Upregulating Major Histocompatibility Complex Class I Molecules

Glasner

Oiknine‐Djian

Weisblum

et al. 2017

J Virol

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NK cells are innate lymphocytes that participate in many immune processes encompassing cancer, bacterial and fungal infection, autoimmunity, and even pregnancy and that specialize in antiviral defense. NK cells express inhibitory and activating receptors and kill their targets when activating signals overpower inhibitory signals. The NK cell inhibitory receptors include a uniquely diverse array of proteins named killer cell immunoglobulin-like receptors (KIRs), the CD94 family, and the leukocyte immunoglobulin-like receptor (LIR) family. The NK cell inhibitory receptors recognize mostly major histocompatibility complex (MHC) class I (MHC-I) proteins. Zika virus has recently emerged as a major threat due to its association with birth defects and its pandemic potential. How Zika virus interacts with the immune system, and especially with NK cells, is unclear. Here we show that Zika virus infection is barely sensed by NK cells, since little or no increase in the expression of activating NK cell ligands was observed following Zika infection. In contrast, we demonstrate that Zika virus infection leads to the upregulation of MHC class I proteins and consequently to the inhibition of NK cell killing. Mechanistically, we show that MHC class I proteins are upregulated via the RIGI-IRF3 pathway and that this upregulation is mediated via beta interferon (IFN-␤). Potentially, countering MHC class I upregulation during Zika virus infection could be used as a prophylactic treatment against Zika virus.IMPORTANCE NK cells are innate lymphocytes that recognize and eliminate various pathogens and are known mostly for their role in controlling viral infections. NK cells express inhibitory and activating receptors, and they kill or spare their targets based on the integration of inhibitory and activating signals. Zika virus has recently emerged as a major threat to humans due to its pandemic potential and its association with birth defects. The role of NK cells in Zika virus infection is largely unknown. Here we demonstrate that Zika virus infection is almost undetected by NK cells, as evidenced by the fact that the expression of activating ligands for NK cells is not induced following Zika infection. We identified a mechanism whereby Zika virus sensing via the RIGI-IRF3 pathway resulted in IFN-␤-mediated upregulation of MHC-I molecules and inhibition of NK cell activity. Countering MHC class I upregulation and boosting NK cell activity may be employed as prophylactic measures to combat Zika virus infection.KEYWORDS Zika virus, MHC class I, NK cells, NK escape mechanisms N K cells are lymphocytes belonging to the innate immune system. NK cells participate in many immunological activities, from killing cancerous cells (1-7) and fighting bacteria (8-10) and fungi (11) to playing roles in allergy (12) and graft-versushost disease (13). NK cells also play roles in autoimmunity (14-18) and pregnancy (19).

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NK Cell Recognition of Candida glabrata through Binding of NKp46 and NCR1 to Fungal Ligands Epa1, Epa6, and Epa7

Cited by 78 publications

References 37 publications

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

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

Functional and phenotypic heterogeneity of group 3 innate lymphoid cells

Zika Virus Escapes NK Cell Detection by Upregulating Major Histocompatibility Complex Class I Molecules

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