IL-2–dependent tuning of NK cell sensitivity for target cells is controlled by regulatory T cells

Gasteiger, Georg; Hemmers, Saskia; Firth, Matthew A.; Floc’h, Audrey Le; Huse, Morgan; Sun, Joseph C.; Rudensky, Alexander Y.

doi:10.1084/jem.20122462

Cited by 173 publications

(159 citation statements)

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“…Our in vitro data demonstrate that this is mediated in part through Treg competition for IL-2, as has been reported in animal models. 20,21 However, we acknowledge that the absence of donor NK cells in patients is likely the consequence of a variety of rejection mechanisms. 8,[22][23][24][25] Direct NK-cell inhibition via Treg membrane-bound transforming growth factor-b has been reported and may also contribute suppression of in vivo NK-cell expansion.…”

Section: Discussionmentioning

confidence: 99%

Clearance of acute myeloid leukemia by haploidentical natural killer cells is improved using IL-2 diphtheria toxin fusion protein

Bachanová¹,

Cooley²,

DeFor

et al. 2014

Blood

354

333

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Key Points• Depletion of host regulatory T cells with IL2DT improves efficacy of haploidentical NK cell therapy for refractory acute myeloid leukemia.• Depletion of Treg and persistence of NK cells for $7 days after NK cell adoptive transfer predicts beneficial clinical responses.Haploidentical natural killer (NK) cell infusions can induce remissions in some patients with acute myeloid leukemia (AML) but regulatory T-cell (Treg) suppression may reduce efficacy. We treated 57 refractory AML patients with lymphodepleting cyclophosphamide and fludarabine followed by NK cell infusion and interleukin (IL)-2 administration. In 42 patients, donor NK cell expansion was detected in 10%, whereas in 15 patients receiving host Treg depletion with the IL-2-diphtheria fusion protein (IL2DT), the rate was 27%, with a median absolute count of 1000 NK cells/mL blood. IL2DT was associated with improved complete remission rates at day 28 (53% vs 21%; P 5 .02) and disease-free survival at 6 months (33% vs 5%; P < .01). In the IL2DT cohort, NK cell expansion correlated with higher postchemotherapy serum IL-15 levels (P 5 .002), effective peripheral blood Treg depletion (<5%) at day 7 (P < .01), and decreased IL-35 levels at day 14 (P 5 .02). In vitro assays demonstrated that Tregs cocultured with NK cells inhibit their proliferation by competition for IL-2 but not for IL-15. Together with our clinical observations, this supports the need to optimize the in vivo cytokine milieu where adoptively transferred NK cells compete with other lymphocytes to improve clinical efficacy in patients with refractory AML. This study is registered at clinicaltrials.gov, identifiers: NCT00274846 and NCT01106950. (Blood. 2014;123(25):3855-3863)

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Section: Discussionmentioning

confidence: 99%

Clearance of acute myeloid leukemia by haploidentical natural killer cells is improved using IL-2 diphtheria toxin fusion protein

Bachanová¹,

Cooley²,

DeFor

et al. 2014

Blood

354

333

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“…Indeed, as reported previously [31], NK cells are sensitive to even limited changes in microRNA content, it is thus possible that differences in the final microRNA level are responsible for the discrepancy. It could also result from indirect effects due to microRNA decrease in other cell types and among them Treg cells [18] or from differences in the timing of Dicer1 deletion. Our results are however in agreement with another study [14].…”

Section: Discussionmentioning

confidence: 99%

“…The caveat of the first study resides in the severe toxicity, especially in the immune system, encountered upon Tamoxifen administration to mice ubiquitously expressing the CreER T2 fusion protein [16]. In addition, "NK-cell" function is conditioned by their interaction with the environment [17,18]; global Dicer1 deletion and microRNA-level decrease might thus affect NK cells in an indirect fashion. The later issue also applies in the work of Sullivan et al Indeed, in this study, Cre expression is driven by the hCD2 promoter also driving Cre expression in the CD4 + regulatory T (Treg) cells compartment.…”

Section: Introductionmentioning

confidence: 99%

“…The later issue also applies in the work of Sullivan et al Indeed, in this study, Cre expression is driven by the hCD2 promoter also driving Cre expression in the CD4 + regulatory T (Treg) cells compartment. Given the known effect of Dicer1 deletion on Treg cells and the importance of Treg cell mediated regulation of "NK-cell" response [18][19][20][21], indirect effects might occur. Moreover, in both studies, the extent of Dicer1 deletion was limited and as much as 50% of the initial microRNA quantity was still present.…”

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confidence: 99%

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NKp46‐mediated Dicer1 inactivation results in defective NK‐cell differentiation and effector functions in mice

et al. 2016

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MicroRNAs control developmental pathways and effector functions in immune cells. Previous studies have studied the role of microRNAs in natural killer (NK) cells. However, the mouse models of microRNA depletion used were nonNK-specific and only partially depleting, hampering the interpretation of the data obtained. To clarify the role of microRNAs in murine NK cells, we deleted the RNase III enzyme Dicer1 in NKp46-expressing cells. We observed a drastic decrease in several microRNAs specifically in NK cells. Furthermore, the overall size of the "NK-cell" pool was severely decreased, a phenotype associated with compromised survival. Moreover, performing a broad flow cytometry profiling, we show that Dicer1-deficient NK cells failed to complete their differentiation program. In particular, several integrins were inappropriately expressed in mature NK cells. These defects coincided with decreased response to IL-15, a cytokine responsible for "NK-cell" maturation and survival. In addition, Dicer1 deletion impaired key "NK-cell" functions: target cell killing and production of IFN-γ, leading to defective control of metastasis. Dicer1 deletion thus affects "NK-cell" biology in a cell intrinsic manner at several distinct stages. Keywords: Cytotoxicity Dicer1 IFN-γ MicroRNA NK cellsAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionNatural killer (NK) cells are group 1 innate lymphoid cells (ILC1) differentiating in the bone marrow (BM) under the influence of Interleukin (IL)-15 [1]. Following commitment to the "NK-cell" lineage, sequential developmental intermediates, from immature to mature, can be defined on the basis of surface expression of Correspondence: Dr. Antoine Marçais e-mail: antoine.marcais@inserm.fr the tumor necrosis factor (TNF) superfamily member CD27 and the integrin CD11b: CD11b lo CD27 hi NK cells (hereafter referred to as "CD11b lo "), CD11b hi CD27 hi (double positive or "DP"), and CD11b hi CD27 lo ("CD27 lo ") [2,3]. In addition, NK cells lose their capacity to proliferate upon maturation, acquire "NK-cell" receptors as well as cytotoxic arsenal, and modify their trafficking machinery to reach peripheral organs where they exert their role of innate sentinels [4]. They have indeed the capacity to kill cells recognized as targets and to produce IFN-γ upon activation, two functions responsible for their role in the defense against intracellular pathogens and in the immunosurveillance of cancer [5]. This C 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2016. 46: 1902-1911 capacity is potentiated by preexposure to IL-15, a process involving the mTOR pathway and granzyme B synthesis [6,7]. Similarly, cytokine stimulation, in particular IL-12/18, triggers secretion of IFN-γ, a property essential to fight intracellular pathogens [1]. Several of these processes might be posttranscriptionally controlled. MicroRNAs are small, noncoding RNAs regulating posttranscriptional gene expression. They are ...

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“…The effect of T-cellderived cytokines may, however, be pleiotropic, and in vitro proliferation is only one readout. For example, T-cell-derived factors may regulate the cytotoxic activity and target-cell recognition of innate lymphocytes (17). In addition, it may be…”

Section: Gliadin-specific T Cells May Activate Iels In Celiac Diseasementioning

confidence: 99%

Is adaptive-innate lymphocyte cross-talk driving mucosal disease?

Gasteiger

2017

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

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IL-2–dependent tuning of NK cell sensitivity for target cells is controlled by regulatory T cells

Abstract: IL-2–dependent adaptive-innate lymphocyte cross talk tunes NK cell reactivity and is limited by T reg cells.

Cited by 173 publications

References 42 publications

Clearance of acute myeloid leukemia by haploidentical natural killer cells is improved using IL-2 diphtheria toxin fusion protein

Clearance of acute myeloid leukemia by haploidentical natural killer cells is improved using IL-2 diphtheria toxin fusion protein

NKp46‐mediated Dicer1 inactivation results in defective NK‐cell differentiation and effector functions in mice

Is adaptive-innate lymphocyte cross-talk driving mucosal disease?

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