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NKG2D Signaling between Human NK Cells Enhances TACE-Mediated TNF-? Release.

ABSTRACT: NK group 2 member D (NKG2D) is a strong NK cell-activating receptor, with engagement by ligands triggering granule release and cytokine production. The function of NKG2D signaling in NK cells has largely been studied in the context of engagement of the receptor by ligands expressed on the surface of target cells. We report that upon activation with IL-12, IL-15, and IL-18 human NK cells express NKG2D ligands of the UL16 binding protein family on the cell surface. NKG2D-ligand interaction between cytokine-stimulated NK cells increases the activity of the metalloprotease TNF-?-converting enzyme. This enhanced TNF-?-converting enzyme activity significantly increases the release of TNF-? and UL16 binding protein from the surface of the NK cells. These results demonstrate that NKG2D signaling is critical for maximal TNF-? release by NK cells. Further, they demonstrate a role for NKG2D-ligand interaction via homotypic NK cell contact in NK cell effector function.

SUBMITTER: Sharma N

PROVIDER: S-EPMC5679425 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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NKG2D Signaling between Human NK Cells Enhances TACE-Mediated TNF-α Release.

Sharma Neekun N Trinidad Camille V CV Trembath Andrew P AP Markiewicz Mary A MA

Journal of immunology (Baltimore, Md. : 1950) 20170911 8

NK group 2 member D (NKG2D) is a strong NK cell-activating receptor, with engagement by ligands triggering granule release and cytokine production. The function of NKG2D signaling in NK cells has largely been studied in the context of engagement of the receptor by ligands expressed on the surface of target cells. We report that upon activation with IL-12, IL-15, and IL-18 human NK cells express NKG2D ligands of the UL16 binding protein family on the cell surface. NKG2D-ligand interaction between ...[more]

PMID: 28893955

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Project description:IntroductionRadiation pneumonitis is a critical complication that constrains the use of radiation therapy for thoracic malignancies, leading to substantial morbidity via respiratory distress and lung function impairment. The role of Natural killer (NK) cells in inflammatory diseases is well-documented; however, their involvement in radiation pneumonitis is not fully understood.MethodsTo explore the involvement of NK cells in radiation pneumonitis, we analyzed tissue samples for NK cell presence and function. The study utilized immunofluorescence staining, western blotting, and immunoprecipitation to investigate CXCL10 and ROS levels, autophagy activity, and NKG2D receptor dynamics in NK cells derived from patients and animal models subjected to radiation.ResultIn this study, we observed an augmented infiltration of NK cells in tissues affected by radiation pneumonitis, although their function was markedly diminished. In animal models, enhancing NK cell activity appeared to decelerate the disease progression. Concomitant with the disease course, there was a notable upsurge in CXCL10 and ROS levels. CXCL10 was found to facilitate NK cell migration through CXCR3 receptor activation. Furthermore, evidence of excessive autophagy in patient NK cells was linked to ROS accumulation, as indicated by immunofluorescence and Western blot analyses. The association between the NKG2D receptor and its adaptor proteins (AP2 subunits AP2A1 and AP2M1), LC3, and lysosomes was intensified after radiation exposure, as demonstrated by immunoprecipitation. This interaction led to NKG2D receptor endocytosis and subsequent lysosomal degradation.ConclusionOur findings delineate a mechanism by which radiation-induced lung injury may suppress NK cell function through an autophagy-dependent pathway. The dysregulation observed suggests potential therapeutic targets; hence, modulating autophagy and enhancing NK cell activity could represent novel strategies for mitigating radiation pneumonitis.

Dataset Information

NKG2D Signaling between Human NK Cells Enhances TACE-Mediated TNF-? Release.

Publications

NKG2D Signaling between Human NK Cells Enhances TACE-Mediated TNF-α Release.

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