Dendritic Cells Support the In Vivo Development and Maintenance of NK Cells via IL-15 Trans-Presentation

Castillo, Eliseo F.; Stonier, Spencer W.; Frasca, Loredana; Schluns, Kimberly S.

doi:10.4049/jimmunol.0900719

Cited by 87 publications

(107 citation statements)

References 53 publications

(82 reference statements)

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“…demonstrated that IL-15Ra of NK cell is dispensable for NK cell homeostasis and Ly49 acquisition (7,11). In this study, we found that IL-15Ra of NK cells is dispensable for mNK cell differentiation and effector function acquisition.…”

Section: Discussionsupporting

confidence: 48%

“…The observation that both types of accessory cells from KI mice fully restored iNK, but not mNK cells suggests that iNK cells require a lower level of IL-15 trans-presentation than mNK cells to achieve normal homeostasis. (11,28,29). We found that the majority of mNK cells in KO mice are at stage 1 (Fig.…”

Section: The Level Of Il-15ra On Bmdcs Determines the Level Of Phosphmentioning

confidence: 99%

“…Previous studies indicate that NK cell homeostasis and mNK differentiation require IL-15Ra of bone marrow (BM)-derived as well as radiation-resistant accessory cells, whereas acquisition of Ly49Rs only requires IL-15Ra of BM-derived accessory cells (7)(8)(9)(10). Overexpression of IL-15Ra by dendritic cells (DCs) in Il15ra 2/2 mice fully supports developing NK cells to acquire effector functions (11). These findings indicate that IL-15 trans-presentation provided by accessory cells is important for NK development.…”

mentioning

confidence: 99%

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Different NK Cell Developmental Events Require Different Levels of IL-15 Trans-Presentation

Lee

Liou

Wang

et al. 2011

The Journal of Immunology

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NK cell development requires IL-15, which is “trans-presented” to IL-15Rβγ on NK cells by IL-15Rα on other cells. In this study, we report that different levels of IL-15 trans-presentation are required for different NK cell developmental events to reach full maturation status. Because the IL-15Rα intracellular domain has the capacity to recruit signaling molecules, we generated knockin and transgenic (Tg) mice that lack the intracellular domain to assess the role of the IL-15 trans-presentation level independent of the function of this domain. The level of IL-15Rα on various cells of these mice follows the order WT > Tg6 > knockin > Tg1 ≥ knockout. Bone marrow (BM)–derived dendritic cells prepared from these mice induced Stat5 phosphorylation in NK cells. The level of phospho-Stat5 correlated with the level of IL-15Rα on BMDCs, thus offering the opportunity to study quantitative effects of IL-15 trans-presentation on NK cell development in vivo. We found that NK cell homeostasis, mature NK cell differentiation, and acquisition of Ly49 receptor and effector functions require different levels of IL-15 trans-presentation input to achieve full status. All NK cell developmental events examined were quantitatively regulated by the IL-15Rα level of BM-derived and radiation-resistant accessory cells, but not by IL-15Rα of NK cells. We also found that IL-15Rα of radiation-resistant cells was more potent than IL-15Rα of BM-derived accessory cells in support of stage 2 to stage 3 splenic mNK differentiation. In summary, each examined developmental event required a particular level of IL-15 trans-presentation by accessory cells.

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Section: Discussionsupporting

confidence: 48%

Section: The Level Of Il-15ra On Bmdcs Determines the Level Of Phosphmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Different NK Cell Developmental Events Require Different Levels of IL-15 Trans-Presentation

Lee

Liou

Wang

et al. 2011

The Journal of Immunology

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“…As opposed to other cytokines that are secreted in soluble form, most IL-15 is transported to the surface of IL-15-producing cells (i.e., dendritic cells and monocytes) in complex with a unique high-affinity receptor, IL-15Ra. The IL-15/IL-15Ra complex is trans-presented to opposing NK, NKT, and mCD8 + T cells expressing IL-2/IL-15Rb and the common g-chain (20)(21)(22)(23)(24). In light of this mechanism of delivery, Rubinstein et al (25) discovered that the combination of IL-15 with the IL-15Ra subunit in solution produced a compound with significantly longer halflife and greater biological activity than native IL-15.…”

mentioning

confidence: 99%

IL-15 Superagonist–Mediated Immunotoxicity: Role of NK Cells and IFN-γ

Guo

Luan

Rabacal

et al. 2015

The Journal of Immunology

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IL-15 is currently undergoing clinical trials to assess its efficacy for treatment of advanced cancers. The combination of IL-15 with soluble IL-15Rα generates a complex termed IL-15 superagonist (IL-15 SA) that possesses greater biological activity than IL-15 alone. IL-15 SA is considered an attractive antitumor and antiviral agent because of its ability to selectively expand NK and memory CD8+ T (mCD8+ T) lymphocytes. However, the adverse consequences of IL-15 SA treatment have not been defined. In this study, the effect of IL-15 SA on physiologic and immunologic functions of mice was evaluated. IL-15 SA caused dose- and time-dependent hypothermia, weight loss, liver injury, and mortality. NK (especially the proinflammatory NK subset), NKT, and mCD8+ T cells were preferentially expanded in spleen and liver upon IL-15 SA treatment. IL-15 SA caused NK cell activation as indicated by increased CD69 expression and IFN-γ, perforin, and granzyme B production, whereas NKT and mCD8+ T cells showed minimal, if any, activation. Cell depletion and adoptive transfer studies showed that the systemic toxicity of IL-15 SA was mediated by hyperproliferation of activated NK cells. Production of the proinflammatory cytokine IFN-γ, but not TNF-α or perforin, was essential to IL-15 SA–induced immunotoxicity. The toxicity and immunological alterations shown in this study are comparable to those reported in recent clinical trials of IL-15 in patients with refractory cancers and advance current knowledge by providing mechanistic insights into IL-15 SA–mediated immunotoxicity.

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“…Therefore, it is plausible that CCR7 may play a crucial role in enabling T cells to "see" IL-7. In contrast, IL-15 is produced by cells of the hematopoietic system, such as dendritic cells (DCs) and macrophages, and is transpresented to T cells via binding to the high-affinity IL-15 receptor α chain (IL-15Rα) expressed on conventional DCs (cDCs) and macrophages (13,(18)(19)(20). IL-15 can be induced by type I IFNs during infection (21,22), but under resting conditions, basal levels of IL-15 aid memory T-cell survival and help replenish the pool of memory CD8 T cells by driving a slow but steady rate of turnover (13).…”

mentioning

confidence: 99%

CCR7 expression alters memory CD8 T-cell homeostasis by regulating occupancy in IL-7– and IL-15–dependent niches

Jung

Kim

Perry

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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C-C receptor 7 (CCR7) is important to allow T cells and dendritic cells to migrate toward CCL19- and CCL21-producing cells in the T-cell zone of the spleen and lymph nodes. The role of this chemokine receptor in regulating the homeostasis of effector and memory T cells during acute viral infection is poorly defined, however. In this study, we show that CCR7 expression alters memory CD8 T-cell homeostasis following lymphocytic choriomeningitis virus infection. Greater numbers of CCR7-deficient memory T cells were formed and maintained compared with CCR7-sufficient memory T cells, especially in the lung and bone marrow. The CCR7-deficient memory T cells also displayed enhanced rates of homeostatic turnover, which may stem from increased exposure to IL-15 as a consequence of reduced exposure to IL-7, because removal of IL-15, but not of IL-7, normalized the numbers of CCR7-sufficient and CCR7-deficient memory CD8 T cells. This result suggests that IL-15 is the predominant cytokine supporting augmentation of the CCR7−/− memory CD8 T-cell pool. Taken together, these data suggest that CCR7 biases memory CD8 T cells toward IL-7–dependent niches over IL-15–dependent niches, which provides insight into the homeostatic regulation of different memory T-cell subsets.

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Dendritic Cells Support the In Vivo Development and Maintenance of NK Cells via IL-15 Trans-Presentation

Cited by 87 publications

References 53 publications

Different NK Cell Developmental Events Require Different Levels of IL-15 Trans-Presentation

Different NK Cell Developmental Events Require Different Levels of IL-15 Trans-Presentation

IL-15 Superagonist–Mediated Immunotoxicity: Role of NK Cells and IFN-γ

CCR7 expression alters memory CD8 T-cell homeostasis by regulating occupancy in IL-7– and IL-15–dependent niches

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