The Association of MHC Class I Proteins with the 2B4 Receptor Inhibits Self-Killing of Human NK Cells

Betser-Cohen, Gili; Mizrahi, Sa’ar; Elboim, Moran; Alsheich-Bartok, Osnat; Mandelboim, Ofer

doi:10.4049/jimmunol.0901572

Cited by 8 publications

(11 citation statements)

References 40 publications

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“…Betser-Cohen et al recently found HLA I proteins coimmunoprecipitate with anti-NKp44 antibodies; reciprocally, NKp44 coimmunoprecipitates with anti-β-2-microglobulin antibodies [17]. Additionally, the Nef protein of HIV prevents surface expression of the activating NKp44 ligand on CD4 infected T cells, which is also consistent with the ability of Nef to retain HLA I intracellularly [18], [19].…”

Section: Introductionmentioning

confidence: 62%

Novel Interaction between Proliferating Cell Nuclear Antigen and HLA I on the Surface of Tumor Cells Inhibits NK Cell Function through NKp44

Horton

Mathew

2013

PLoS ONE

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NK cell function is closely regulated by numerous inhibitory and activating receptors binding corresponding ligands on the surface of target cells, providing vital first line defenses against infections and cancer. NKp44, originally discovered as an activating NK cell receptor, was recently found to elicit inhibitory effects on NK cell effector function through recognition of cell surface PCNA. Other reports have pointed to potential associations between NKp44 and HLA I molecules, as well as HLA I and Damage Associated Molecular Pattern molecules (DAMPs) on the surface of tumor cells. In this report, we have identified novel interaction between HLA I and PCNA on the surface of human tumor cells by confocal microscopy and immunoprecipitation. In addition to previous reports, we show PCNA on the cell surface where novel association with HLA I does not require the presence of NKp44 expressing NK cells and occurs with endogenous PCNA. The association of HLA I and PCNA forms the inhibitory ligand for NKp44, resulting in inhibition of NK cell cytotoxicity. We further postulate NCR ligands are composed of DAMP molecules localized to the cell surface, colocalizing with HLA I, and potentially heparin sulfate proteoglycans.

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Section: Introductionmentioning

confidence: 62%

Novel Interaction between Proliferating Cell Nuclear Antigen and HLA I on the Surface of Tumor Cells Inhibits NK Cell Function through NKp44

Horton

Mathew

2013

PLoS ONE

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“…Instead, it appeared to be tightly controlled by MHC class I in human NK cells [21] and by collective and simultaneous engagement of other NK receptors, e.g., LFA-1 and NKG2D [22,23]. Thus, human NK cells are protected from autologous lysis by 2B4 via at least 2 mechanisms: suppression of 2B4 by MHC class I and cross-talk among other receptors.…”

Section: Discussionmentioning

confidence: 88%

Unidirectional signaling triggered through 2B4 (CD244), not CD48, in murine NK cells

Kim¹,

Kim²,

Kim³

et al. 2010

Journal of Leukocyte Biology

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Engagement of 2B4 (CD244) with CD48 results in activation, costimulation, or inhibition of NK cell activities, depending on the cell types and the stage of differentiation. In vivo, 2B4+ NK cells can interact with CD48+ NK cells and also with surrounding CD48+ hematopoietic cells. Similarly, CD48+ NK cells may be triggered by adjacent 2B4+ NK cells or other hematopoietic cells expressing 2B4, e.g., monocytes, basophils, γδ T cells, etc. As CD48 was also shown to function as an activating receptor, 2B4/CD48 binding in the settings of NK-to-NK or NK-to-non-NK cell interactions may generate bidirectional signals. To address this question, we examined the consequence of CD48 or 2B4 ligation using two experimental settings: one with target (syngeneic EL4 and allogeneic P815) cells, ectopically expressing surface 2B4 or CD48, and the other with direct cross-linking with plate-bound mAb. Here, we report that ligation of CD48 with 2B4+ EL4 or 2B4+ P815 targets, in the absence of other receptor engagement, did not alter NK cell cytotoxicity or proliferation significantly. Similarly, cross-linking of NK cells with plate-bound anti-CD48 mAb in the absence or presence of a suboptimal dose of IL-2 did not modulate NK proliferation, cytotoxicity, or cytokine production. Nonetheless, 2B4 cross-linking promoted NK cell proliferation and effector functions consistently in both settings. Therefore, our results demonstrate unequivocally that CD48 on surrounding NK or non-NK cells serves primarily as a ligand to stimulate 2B4 on the adjacent NK cells in mice.

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“…The RCDII lines also had higher expression levels of SH2 domain containing 1B (SH2D1B/EAT-2) which can act as an adapter molecule for the cell surface receptors CD84, CD244 and CD150 (SLAMF1) 27. All RCDII cell lines expressed CD244 (table 1), a receptor expressed by NK cells and effector/memory T cells,28 while SLAMF1 expression was downregulated in the RCDII cell lines. In addition, several other genes that are associated with T-cell mediated immunity according to the PANTHER classification were downregulated in the RCDII lines compared with the T-cell lines, in particular granulysin (GNLY), lymphotoxin β (LTB) and tumour necrosis factor receptor 4 (figure 1A,B).…”

Section: Resultsmentioning

confidence: 99%

Identification of a potential physiological precursor of aberrant cells in refractory coeliac disease type II

Schmitz

Tjon

Lai

et al. 2012

Gut

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The Association of MHC Class I Proteins with the 2B4 Receptor Inhibits Self-Killing of Human NK Cells

Cited by 8 publications

References 40 publications

Novel Interaction between Proliferating Cell Nuclear Antigen and HLA I on the Surface of Tumor Cells Inhibits NK Cell Function through NKp44

Novel Interaction between Proliferating Cell Nuclear Antigen and HLA I on the Surface of Tumor Cells Inhibits NK Cell Function through NKp44

Unidirectional signaling triggered through 2B4 (CD244), not CD48, in murine NK cells

Identification of a potential physiological precursor of aberrant cells in refractory coeliac disease type II

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