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An XBP1s-PIM-2 positive feedback loop controls IL-15-mediated survival of natural killer cells

ABSTRACT: We previously reported that XBP1s, an essential transcription factor downstream of IL-15 and AKT signaling, controls cell survival and effector functions of human natural killer (NK) cells. However, the precise mechanisms remain unknown. In this study, by using XBP1 conditional knock-out mice, we found that XBP1s is critical for IL-15-mediated NK cell survival but not proliferation in vitro and in vivo. Mechanistically, XBP1s regulates homeostatic NK cell survival through targeting PIM-2, a critical anti-apoptotic gene, which in turn stabilizes XBP1s protein by phosphorylating it at Thr58. In addition, XBP1s enhances the effector functions and anti-tumor immunity of NK cells by recruiting T-bet to the promoter region of Ifng. Collectively, our findings identify a previously unknown mechanism by which IL-15–XBP1s signaling regulates the survival and effector functions of NK cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE218543 | GEO | 2022/12/31

REPOSITORIES: GEO

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Xbp1s controls IL-15-mediated natural killer cell survival and function by regulating Pim2 and Tbet

Project description:We previously reported that X-Box Binding Protein 1 (Xbp1s), an essential transcriptional factor downstream of IL-15 and Akt signaling, controls cell survival and effector function in human natural killer (NK) cells. However, the mechanisms by which Xbp1s regulates NK cell survival and function remains unknown. In this study, by using Xbp1s conditional knock-out (KO) mice, we found that Xbp1s is critical for IL-15-mediated NK cell survival but not proliferation in vitro and in vivo. Mechanically, Xbp1s regulates homeostatic NK cell survival through targeting Pim2, a critical anti-apoptotic gene. Pim2 in turn stabilizes Xbp1s protein through phosphorylation at Thr58. Xbp1s enhances NK cell effector function and anti-tumor immunity via recruitment of Tbet to the promoter region of Ifng. Collectively, our findings reveal an important role of IL-15–Xbp1s signaling in NK cell survival and effector function.

2022-12-31 | GSE188796 | GEO

Transcriptome analysis PIM kinase inhibition vs degradation

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2023-12-04 | GSE237256 | GEO

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Project description:T cell antigen-receptor (TCR) and cytokine receptor engagement trigger large changes in Serine/Threonine kinase signalling networks to drive T cell activation and differentiation. The role of only few kinase signalling pathways have been studied in detail, and in this context, Pim kinases are an interesting, yet understudied, family of Serine/Threonine kinases, with reported roles in key processes including survival, proliferation, metabolism across a range of cell types. T lymphocytes predominantly express PIM1 and PIM2, which are rapidly induced by TCR, costimulation and cytokine signalling. Using high-resolution mass spectrometry and RNAseq we systematically examine the impact of Pim1/Pim2 double deficiency on in vitro differentiated cytotoxic T lymphocytes (CTL) expanded in the cytokines IL-2 and IL-15 to generate effector or memory T cells respectively. We find that Pim kinases are dispensable for IL-15-driven memory cell differentiation, but that Pim1/2-deficiency has a selective impact on the transcriptome and proteome of IL-2 driven effector CD8 T cells. ~75% of Pim kinase-regulated proteins were not predicted by differences in mRNA in IL-2 expanded CTL. These included proteins that are key for effector cell function: glucose transporters SLC2A1 and SLC2A3 and key effector molecules Granzyme A and B. We find that Pim kinases have this effect via control of protein translation. Another key finding was that the mRNA for key T cell homing receptors Ccr7, S1pr1 and CD62L was increased in Pim1/2-deficienct T cells and that this functionally enhancing homing to secondary lymphoid organs.

2024-04-15 | PXD051213 | Pride

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2023-12-31 | GSE243385 | GEO

Effect of anti-IL-15 administration on T cell and NK cell homeostasis in rhesus macaques (TCM)

Project description:Analysis of the effect of anti-IL-15 monoclonal antibody treatment on T cell and NK cell homeostasis in rhesus macaques. The hypothesis tested in the present study was that repeated administrations of a rhesusized anti-IL-15 monoclonal antibody would block IL-15 activity in vivo and result in changes to T and/or NK cell population dynamics that would reflect physiologic IL-15 function. The results provide important information on the specific role IL-15 plays in effector memory T cell and NK cell homeostasis, noting that effector memory T cells but not NK cells can be maintained in the absence of IL-15 signaling by the activity of other cytokines. Sort-purified CD8+ and CD4+ TCM from PBMC, before and after treatment with IgG1 Ab and anti-IL15 Ab

2016-09-07 | E-GEOD-76785 | biostudies-arrayexpress

Effect of anti-IL-15 administration on T cell and NK cell homeostasis in rhesus macaques (TEM)

Project description:Analysis of the effect of anti-IL-15 monoclonal antibody treatment on T cell and NK cell homeostasis in rhesus macaques. The hypothesis tested in the present study was that repeated administrations of a rhesusized anti-IL-15 monoclonal antibody would block IL-15 activity in vivo and result in changes to T and/or NK cell population dynamics that would reflect physiologic IL-15 function. The results provide important information on the specific role IL-15 plays in effector memory T cell and NK cell homeostasis, noting that effector memory T cells but not NK cells can be maintained in the absence of IL-15 signaling by the activity of other cytokines. Sort-purified CD8+ TEM from PBMC, before and after treatment with IgG1 Ab and anti-IL15 Ab

2016-09-07 | E-GEOD-76796 | biostudies-arrayexpress

Effect of anti-IL-15 administration on T cell and NK cell homeostasis in rhesus macaques (TEM)

2016-09-07 | GSE76796 | GEO

Effect of anti-IL-15 administration on T cell and NK cell homeostasis in rhesus macaques (TCM)

2016-09-07 | GSE76785 | GEO

IL-15-DEPENDENT IMMUNE CROSS-TALK BETWEEN NK CELLS AND DENDRITIC CELLS IN HIV-1 ELITE CONTROLLERS [CUT&RUN]

Project description:As the principal effector cell population of the innate immune system, NK cells may make critical contributions to natural, immune-mediated control of HIV-1 replication. Using genome-wide assessments of activating and inhibitory epigenetic chromatin features, we here demonstrate that cytotoxic NK (cNK) cells from elite controllers (ECs) frequently display elevated activating histone modifications at the IL-2/IL-15 receptor β chain and the BCL-2 gene loci. These epigenetic changes translated into increased responsiveness of cNK cells to paracrine IL-15 secretion, which coincided with higher levels of IL-15 transcription by myeloid dendritic cells in ECs. The distinct immune crosstalk between these two innate immune cell populations resulted in improved IL-15-dependent cNK cell survival, paired with a metabolic profile biased towards IL-15-mediated glycolytic activities. Together, these results suggest that cNK cells from ECs display an epigenetically-programmed IL-15 response signature, and support the emerging role of innate immune pathways in natural, drug-free control of HIV-1.

2023-12-06 | GSE232915 | GEO

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