CD161 (Human NKR-P1A) Signaling in NK Cells Involves the Activation of Acid Sphingomyelinase

Pozo, David; Valés‐Gómez, Mar; Mavaddat, Nasim; Williamson, S; Chisholm, Susan E.; Reyburn, Hugh

doi:10.4049/jimmunol.176.4.2397

Cited by 72 publications

(93 citation statements)

References 72 publications

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“…It has been reported that CD161 directly interacts with ASM in NK cells. The interaction can activate ASM enzymatic activity and induce subsequent intracellular signals inclusive of protein kinase B (Akt) and, thus, regulate NK cell function [8]. We have further confirmed that in human CD4 + T cells, ASM directly interacts with CD39 and CD161, respectively.…”

supporting

confidence: 62%

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Beyond ecto-nucleotidase: CD39 defines human Th17 cells with CD161

Bai

Robson

2015

Purinergic Signalling

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CD39/ENTPD1 is a prototypic member of the ectonucleoside triphosphate diphosphohydrolase (ENTPDase) family on cell surface. CD39 has been reported to be a marker of regulatory immune cells and catalyzes extracellular hydrolysis of nucleotides to generate AMP and, in tandem with CD73, adenosine. We have recently found in addition that co-expression of CD39 and CD161 by human CD4 + T cells may become a biomarker of human Th17 cells. CD39 and CD161 have direct interactions that are further linked with acid sphingomyelinase (ASM). Upon activation of CD39 and CD161, the molecular interactions boost ASM bio-activity, which generates cellular ceramide to further mediate downstream signals inclusive of STAT3 and mTOR. We suggest modulation of human Th17 responsiveness by CD39 and CD161 and describe novel molecular mechanisms integrating elements of both extracellular nucleotide and sphingolipid homeostasis that are pivotal in the control of human Th17 cells and which could have therapeutic potential.

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supporting

confidence: 62%

“…ASM, a lipid hydrolase, plays a pivotal role in mediating a variety of signals by degrading sphingomyelin into ceramide [8]. Ceramide is an important messenger in response to cell proliferation, differentiation, and apoptosis.…”

mentioning

confidence: 99%

Beyond ecto-nucleotidase: CD39 defines human Th17 cells with CD161

Bai

Robson

2015

Purinergic Signalling

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“…45 Further analysis of CD161 signaling pathway in T lymphocytes indicated that CD161 triggers the activation of the PI3K-PKB/Akt-1 pathway. 36 This study shows that the PI3K-PKB/ Akt-1 pathway is activated by CD161 cross-linking in immNK cells. The ability of CD161 to function either as inhibitory or activating receptor is still a matter of debate.…”

Section: Discussionmentioning

confidence: 98%

Human NK cells at early stages of differentiation produce CXCL8 and express CD161 molecule that functions as an activating receptor

Montaldo

Vitale

Cottalasso

et al. 2012

Blood

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Human natural killer (NK) cell development is a step-by-step process characterized by phenotypically identified stages. CD161 is a marker informative of the NK cell lineage commitment, whereas CD56, CD117, and CD94/NKG2A contribute to define discrete differentiation stages. In cells undergoing in vitro differentiation from CD34 ؉ umbilical cord blood (UCB) progenitors, LFA-1 expression allowed to discriminate between immature noncytolytic CD161 ؉ CD56 ؉ LFA-1 ؊ and more differentiated cytolytic CD161 ؉ CD56 ؉ LFA-1 ؉ NK cells. CD161 ؉ CD56 ؉ LFA-1 ؊ NK cells produce large amounts of CXCL8 after phorbol myristate acetate (PMA) or cytokine treatment. Remarkably, CXCL8 mRNA expression was also detected in fresh stage III immature NK cells isolated from tonsils and these cells expressed CXCL8 protein on PMA stimulation. Within in vitro UCB-derived CD161 ؉ CD56 ؉ LFA-1 ؊ NK cells, CXCL8 release was also induced on antibodymediated cross-linking of NKp44 and CD161. Such unexpected activating function of CD161 was confined to the CD161 ؉ CD56 ؉ LFA-1 ؊ subset, because it did not induce cytokine release or CD107a expression in CD161 ؉ CD56 ؉ LFA-1 ؉ cells or in mature peripheral blood NK cells. Anti-CXCL8 neutralizing antibody induced a partial inhibition of NK cell differentiation, which suggests a regulatory role of CXCL8 during early NK cell differentiation. Altogether, these data provide novel information that may offer clues to optimize NK cell maturation in hematopoietic stem cell transplantation. (Blood. 2012; 119(17):3987-3996) IntroductionNatural killer (NK) cells play a key role in the host defense because of their ability to mediate cytolytic activity and to release cytokines during the early phases of immune responses against tumor cells, viruses, and other pathogens. [1][2][3] In humans, two main cell subsets have been identified: CD3 Ϫ CD56 dim CD16 ϩ cells (CD56 dim ), which represent the majority of NK cells circulating in the peripheral blood (PB) and CD3 Ϫ CD56 bright CD16 Ϫ cells (CD56 bright ), that are a minority in PB but are largely represented in peripheral tissues. These subsets differ for the expression and the surface density of the main inhibitory receptors. Thus, killer immunoglobulin (Ig)-like receptors (KIR), specific for HLA-class I allotypes are confined to CD56 dim cells (that may also express the HLA-Especific CD94/NKG2A receptor), whereas CD56 bright cells express CD94/NKG2A but not KIRs. 2,4,5 Cytolytic activity is mostly associated with the CD56 dim subset, whereas CD56 bright NK cells are poorly cytotoxic but secrete cytokines playing an immunoregulatory role in innate and in adaptive immunity. 2,5,6 Recent data demonstrated that the "cytolytic" CD56 dim subset also releases large amounts of cytokines within a short time interval after receptor-mediated activation. Thus, CD56 dim cells may provide a prompt intervention mediating not only rapid killing, but also production of proinflammatory cytokines and chemokines. 7,8 On the other hand, CD56 bright cells would guarantee a late, b...

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“…Samples were diluted with an equal volume of 85% sucrose in TNE and then placed at the bottom of a step sucrose gradient and fractionated by centrifugation for 18 -20 h at 200,000 ϫ g (25). One-milliliter fractions were collected from top to bottom and made to a final concentration of 0.2% deoxycholate.…”

Section: Detergent-resistant Membrane (Drm) Fractionationmentioning

confidence: 99%

Brief Residence at the Plasma Membrane of the MHC Class I-Related Chain B Is Due to Clathrin-Mediated Cholesterol-Dependent Endocytosis and Shedding

Agüera-González

Boutet

Reyburn

et al. 2009

The Journal of Immunology

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Recognition of MHC class I-related chain (MIC) molecules on the surface of target cells by the activating receptor NKG2D leads to their lysis by immune effector cells. Up-regulation of NKG2D ligands is broadly related to stress, although the detailed molecular mechanisms that control the presence of these molecules at the plasma membrane are unclear. To investigate the posttranslational mechanisms that control surface expression of the human NKG2D ligand MICB, we studied the subcellular localization and trafficking of this molecule. We found that in several cellular systems, the expression of MICB molecules on the cell surface is accompanied by an intracellular accumulation of the molecule in the trans-Golgi network and late endosome-related compartments. Surprisingly, MICB has a much shorter half-life at the plasma membrane than MHC molecules and this depends on both recycling to internal compartments and shedding to the extracellular medium. Internalization of MICB depends partially on clathrin, but importantly, the lipid environment of the membrane also plays a crucial role in this process. We suggest that the brief residence of MICB at the plasma membrane modulates, at least in part, the function of this molecule in the immune system. The Journal of Immunology, 2009, 182: 4800 -4808. M ajor histocompatibility complex class I-related chain (MIC)4 A and B are two MHC-like molecules encoded within the human MHC, but distinct from classical HLA class I proteins in that they bind neither ␤ 2 -microglobulin nor antigenic peptides (1-4). MIC proteins bind the activating receptor NKG2D that is constitutively expressed on all NK cells and CD8 ϩ T cell subpopulations and is upregulated after activation on CD4 ϩ T cells (5). Engagement of NKG2D by its ligands leads to the activation of lysis and cytokine secretion by NK cells and T cells either directly or as a costimulatory factor (for review, see Ref. 6). Thus, the presence of MIC at the surface of putative target cells must be tightly regulated so that the immune response is not triggered or hidden inappropriately (which would lead to autoimmunity in the first instance and immune evasion in the latter). In fact, with the exception of gastrointestinal epithelium, the vast majority of normal cells do not express MIC molecules at the cell surface; instead, the expression of these proteins is up-regulated in a number of pathological situations, mainly cancer and autoimmunity (for review, see Refs. 7 and 8). For example, MIC expression has been found in tumors of various origins and the presence of pathogens like Mycobacterium tuberculosis has been shown to up-regulate its expression (9). Recently, a number of external stimuli such as DNA-damaging agents and proteasome inhibitors have been shown to induce expression of NKG2D ligands (10, 11). Thus, although the precise mechanisms that regulate MIC expression are still unknown, the presence of MIC at the plasma membrane can be related broadly with stress and this coincides with the presence of heat shock elements in the M...

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CD161 (Human NKR-P1A) Signaling in NK Cells Involves the Activation of Acid Sphingomyelinase

Cited by 72 publications

References 72 publications

Beyond ecto-nucleotidase: CD39 defines human Th17 cells with CD161

Beyond ecto-nucleotidase: CD39 defines human Th17 cells with CD161

Human NK cells at early stages of differentiation produce CXCL8 and express CD161 molecule that functions as an activating receptor

Brief Residence at the Plasma Membrane of the MHC Class I-Related Chain B Is Due to Clathrin-Mediated Cholesterol-Dependent Endocytosis and Shedding

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