Stage-Specific Requirement for Eomes in Mature NK Cell Homeostasis and Cytotoxicity

Wagner, Julia A.; Wong, Pamela; Schappe, Timothy; Berrien-Elliott, Melissa M.; Cubitt, Celia C.; Jaeger, Natália; Lee, Madeline; Keppel, Catherine R.; Marín, Nancy D.; Foltz, Jennifer A.; Marsala, Lynne; Neal, Carly C.; Sullivan, Ryan P.; Schneider, Stephanie; Keppel, Molly P.; Saucier, Nermina; Cooper, Megan A.; Fehniger, Todd A.

doi:10.1016/j.celrep.2020.107720

Cited by 51 publications

(62 citation statements)

References 53 publications

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“…The enrichment step not only serves to increase the percentage of NK cells in the resulting enriched sample but also normalize the NK cell percentages in experimental groups that could have started with different NK cell numbers. In our experience, the purity after enrichment is similar between groups in each experiment even if they had different NK cell percentages to start as we did in Wagner et al. (2020) .…”

Section: Step-by-step Methods Detailsmentioning

confidence: 58%

“…For each E:T ratio, Percent Specific Killing is calculated as [% 7-AAD+ of CTV+ cells] (Effector+Target) well – [%7-AAD+ of CTV+ cells] Target only well . In a killing assay performed C57BL/6 mice with wild-type NK cells against RMA-S targets, the %specific killing should be around 50% at 5:1 enriched NK : RMA-S as reported in Wagner et al. (2020) and also Figure 3 B here.…”

Section: Expected Outcomesmentioning

confidence: 54%

“…This protocol details specifically an ex vivo cytotoxicity assay using primary murine NK cells enriched from splenocytes that were activated in vivo with poly(I:C). For complete details on the use and execution of this protocol, please refer to Wagner et al. (2020) .…”

mentioning

confidence: 99%

“…For complete details on the use and execution of this protocol, please refer to Wagner et al. (2020) .…”

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confidence: 99%

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Flow cytometry-based ex vivo murine NK cell cytotoxicity assay

et al. 2021

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Section: Step-by-step Methods Detailsmentioning

confidence: 58%

Section: Expected Outcomesmentioning

confidence: 54%

mentioning

confidence: 99%

“…For complete details on the use and execution of this protocol, please refer to Wagner et al. (2020) .…”

mentioning

confidence: 99%

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Flow cytometry-based ex vivo murine NK cell cytotoxicity assay

et al. 2021

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“…Consistently, mice harboring genomic deletions of T-bet and Eomes lack NK cells, but CD122 hi precursors of NK cells were observed ( 36 ). In addition, the deletion of Eomes in mice results in significantly decreased CD122 expression at different stages of NK cell maturation ( 33 , 35 , 37 ). Moreover, Eomes + NK cells express more CD122 and proliferate better than Eomes − NK cells, which are called Innate Lymphoid Cells (ILCs) 1 now ( 38 , 39 ).…”

Section: When Does Il-15 Promote Nk Cell Development?mentioning

confidence: 99%

Transcription Factors Associated With IL-15 Cytokine Signaling During NK Cell Development

Wang

Zhao

2021

Front. Immunol.

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Natural killer (NK) cells are lymphocytes primarily involved in innate immunity and possess important functional properties in anti-viral and anti-tumor responses; thus, these cells have broad potential for clinical utilization. NK cells originate from hematopoietic stem cells (HSCs) through the following two independent and continuous processes: early commitment from HSCs to IL-15-responsive NK cell progenitors (NKPs) and subsequent differentiation into mature NK cells in response to IL-15. IL-15 is the most important cytokine for NK cell development, is produced by both hematopoietic and nonhematopoietic cells, and functions through a distinct delivery process termed transpresentation. Upon being transpresented to NK cells, IL-15 contributes to NK cell development via the activation of several downstream signaling pathways, including the Ras–MEK–MAPK, JAK–STAT5, and PI3K–ATK–mTOR pathways. Nonetheless, the exact role of IL-15 in NK cell development has not been discussed in a consecutive and comprehensive manner. Here, we review current knowledge about the indispensable role of IL-15 in NK cell development and address which cells produce IL-15 to support NK cell development and when IL-15 exerts its function during multiple developmental stages. Specifically, we highlight how IL-15 supports NK cell development by elucidating the distinct transpresentation of IL-15 to NK cells and revealing the downstream target of IL-15 signaling during NK cell development.

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Checkpoint TIPE2 Limits the Helper Functions of NK Cells in Supporting Antitumor CD8⁺ T Cells

Jin

Zheng

et al. 2023

Advanced Science

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Natural killer (NK) cells not only are innate effector lymphocytes that directly participate in tumor surveillance but are also essential helpers in the antitumor CD8 + T-cell response. However, the molecular mechanisms and potential checkpoints regulating NK cell helper functions remain elusive. Here, it is shown that the T-bet/Eomes-IFN-𝜸 axis in NK cells is essential for CD8 + T cell-dependent tumor control, whereas T-bet-dependent NK cell effector functions are required for an optimal response to anti-PD-L1 immunotherapy. Importantly, NK cell-expressed TIPE2 (tumor necrosis factor-alpha-induced protein-8 like-2) represents a checkpoint molecule for NK cell helper function, since Tipe2 deletion in NK cells not only enhances NK-intrinsic antitumor activity but also indirectly improves the antitumor CD8 + T cell response by promoting T-bet/Eomes-dependent NK cell effector functions. These studies thus reveal TIPE2 as a checkpoint for NK cell helper function, whose targeting might boost the antitumor T cell response in addition to T cell-based immunotherapy.

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Stage-Specific Requirement for Eomes in Mature NK Cell Homeostasis and Cytotoxicity

Cited by 51 publications

References 53 publications

Flow cytometry-based ex vivo murine NK cell cytotoxicity assay

Flow cytometry-based ex vivo murine NK cell cytotoxicity assay

Transcription Factors Associated With IL-15 Cytokine Signaling During NK Cell Development

Checkpoint TIPE2 Limits the Helper Functions of NK Cells in Supporting Antitumor CD8⁺ T Cells

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Stage-Specific Requirement for Eomes in Mature NK Cell Homeostasis and Cytotoxicity

Cited by 51 publications

References 53 publications

Flow cytometry-based ex vivo murine NK cell cytotoxicity assay

Flow cytometry-based ex vivo murine NK cell cytotoxicity assay

Transcription Factors Associated With IL-15 Cytokine Signaling During NK Cell Development

Checkpoint TIPE2 Limits the Helper Functions of NK Cells in Supporting Antitumor CD8+ T Cells

Contact Info

Product

Resources

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Checkpoint TIPE2 Limits the Helper Functions of NK Cells in Supporting Antitumor CD8⁺ T Cells