Phospho-proteomics reveals that RSK signaling is required for proliferation of natural killer cells stimulated with IL-2 or IL-15

MacMullan, Melanie A.; Wang, Pin; Graham, Nicholas

doi:10.1016/j.cyto.2022.155958

Cited by 3 publications

(2 citation statements)

References 93 publications

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“…STK17B encodes the serine/threonine-protein kinase 17B, associated with T cell differentiation, activation and survival (Mandarano et al, 2020; Ryan and Craig, 2011). Phosphorylation of STK17B was upregulated in NK cells upon IL-2 and IL-15 stimulation (MacMullan et al, 2022). EPHA4 encodes ephrin type-A receptor 4, which phosphorylates proline-rich tyrosine kinase 2, regulating the cytotoxic response between NK and target cells (Sancho et al, 2000; Aasheim et al, 2005).…”

Section: Resultsmentioning

confidence: 99%

A robust platform for BaEVRless-lentiviral synthesis and primary natural killer cell transduction

Lan,

Nguyen,

Chao

et al. 2024

Preprint

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Lentiviral vectors are invaluable tools for genetic modification in human cells for research, biotechnological and clinical applications. However, certain cell types, such as primary human natural killer (NK) cells, present challenges in lentiviral transduction. Overcoming this limitation requires specific pseudotype modifications. BaEVRless-pseudotyped lentivirus (BaEVRless-LV) has shown promise in efficiently transducing human NK cells, B cells, and hematopoietic stem cells (HSCs). BaEVRless, a modified envelope protein derived from Baboon endogenous retrovirus, targets ASCT receptors in human cells. While effective for several immune cell types, BaEVRless-LV production in standard HEK293T cells is challenging. During lentiviral synthesis, BaEVRless protein induces hyper cell fusion, leading to rapid HEK293T cell death and reduced BaEVRless-LV titers. To solve this problem, we used CRISPR genome editing to knockout (KO) the ASCT2 gene in HEK293T cells, thereby abolishing BaEVRless-induced cell fusion. Using the ASCT2-KO cells and an optimized viral production protocol, we efficiently packaged high titers of BaEVRless-LV encoding various transgenes, including turbogfp, chimeric antigen receptor (CAR), and a pooled CRISPR sgRNA library. Our robust BaEVRless-LV synthesis platform is readily adaptable for manufacturing cell therapeutics and enables advanced research techniques such as CRISPR genetic screens in primary NK cells.

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Section: Resultsmentioning

confidence: 99%

A robust platform for BaEVRless-lentiviral synthesis and primary natural killer cell transduction

Lan,

Nguyen,

Chao

et al. 2024

Preprint

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“…IL-15 treatment activates mTORC1, which increases cellular metabolism [ 16 ]. IL-15 also activates STAT5, AKT [ 16 ], ERK [ 78 ] and its downstream target RSK [ 79 ]. Several studies have investigated the role of these different proteins in the activation of mTORC1.…”

Section: Mtor Activation Downstream Of γC Cytokine Receptors In Lymph...mentioning

confidence: 99%

Signaling Pathways Leading to mTOR Activation Downstream Cytokine Receptors in Lymphocytes in Health and Disease

Fallone

Walzer

Marçais

2023

IJMS

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CD8+ T cells and Natural Killer (NK) cells are cytotoxic lymphocytes important in the response to intracellular pathogens and cancer. Their activity depends on the integration of a large set of intracellular and environmental cues, including antigenic signals, cytokine stimulation and nutrient availability. This integration is achieved by signaling hubs, such as the mechanistic target of rapamycin (mTOR). mTOR is a conserved protein kinase that controls cellular growth and metabolism in eukaryotic cells and, therefore, is essential for lymphocyte development and maturation. However, our current understanding of mTOR signaling comes mostly from studies performed in transformed cell lines, which constitute a poor model for comprehending metabolic pathway regulation. Therefore, it is only quite recently that the regulation of mTOR in primary cells has been assessed. Here, we review the signaling pathways leading to mTOR activation in CD8+ T and NK cells, focusing on activation by cytokines. We also discuss how this knowledge can contribute to immunotherapy development, particularly for cancer treatment.

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Immunosuppressive effects of triptolide via interleukin-2/receptor signaling

Xiong,

Yin,

Darshika Kodithuwakku

et al. 2024

Immunopharmacology and Immunotoxicology

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Phospho-proteomics reveals that RSK signaling is required for proliferation of natural killer cells stimulated with IL-2 or IL-15

Cited by 3 publications

References 93 publications

A robust platform for BaEVRless-lentiviral synthesis and primary natural killer cell transduction

A robust platform for BaEVRless-lentiviral synthesis and primary natural killer cell transduction

Signaling Pathways Leading to mTOR Activation Downstream Cytokine Receptors in Lymphocytes in Health and Disease

Immunosuppressive effects of triptolide via interleukin-2/receptor signaling

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