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Proliferation conditions promote intrinsic changes in NK Cells for an IL-10 response

ABSTRACT: Constitutively found at high frequencies, the role for NK cell proliferation remains unclear. Here, a shift in NK cell function from predominantly producing interferon-? (IFN-?), a cytokine with proinflammatory and antimicrobial functions, to producing the immunoregulatory cytokine IL-10, is defined during extended murine cytomegalovirus infection. The NK cells driven to express IL-10 in vivo acquired responsiveness to IL-12 and IL-21 for IL-10 production, but neither cytokine was required for the endogenous response. In vitro studies with IL-2 to support proliferation and in vivo adoptive transfers into murine cytomegalovirus-infected mice demonstrated that NK cell proliferation and further division enhanced the change. During infection, the responding NK cells acquired histone modifications indicative of an open IL-10 gene, and an IL-10 response was proliferation dependent ex vivo if the NK cells had not yet expanded in vivo but independent if they had. Thus, a novel role for proliferation in supporting changing innate cell function is discovered. The chromatin status of ex vivo isolated NK cells during MCMV infection was investigated by ChIP-seq on histone epigenetic marks (H3K4m3, H3K27m3, H3K36m3) on day 0, day 1.5 and day 3.5 post infection.

ORGANISM(S): Mus musculus

SUBMITTER: Yuka Kanno

PROVIDER: E-GEOD-55834 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Proliferation conditions promote intrinsic changes in NK cells for an IL-10 response.

Tarrio Margarite L ML Lee Seung-Hwan SH Fragoso Maria F MF Sun Hong-Wei HW Kanno Yuka Y O'Shea John J JJ Biron Christine A CA

Journal of immunology (Baltimore, Md. : 1950) 20140606 1

Constitutively found at high frequencies, the role for NK cell proliferation remains unclear. In this study, a shift in NK cell function from predominantly producing IFN-γ, a cytokine with proinflammatory and antimicrobial functions, to producing the immunoregulatory cytokine IL-10 was defined during extended murine CMV infection. The response occurred at times subsequent to IL-12 production, but the NK cells elicited acquired responsiveness to IL-12 and IL-21 for IL-10 production. Because neith ...[more]

PMID: 24907347

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Project description:Treatment of hematological malignancies by adoptive transfer of activated natural killer (NK) cells is limited by poor post-infusion persistence. We compared the ability of interleukin-2 (IL-2) and IL-15 to sustain human NK cell functions following cytokine withdrawal to model post-infusion performance. In contrasts to IL-2, IL-15 mediated stronger signaling through the IL-2/15 receptor complex and provided functional advantages. Genome-wide analysis of cytosolic and polysome-associated mRNA revealed cytokine dependent differential mRNA levels and translation during cytokine activation but also that most gene expression differences were primed by IL-15 and only manifested after cytokine withdrawal. IL-15 augmented mTOR signaling, which correlated with increased expression of genes related to cell metabolism and respiration. Consistently, mTOR inhibition abrogated IL-15-induced functional advantages. Moreover, mTOR-independent STAT-5 signaling contributed to improved NK cell function during cytokine activation but not following cytokine withdrawal. The superior performance of IL-15 stimulated NK cells was also observed using a clinically applicable protocol for NK cell expansion. Finally, expression of IL-15 correlated with cytolytic immune functions in patients with B cell lymphoma and favorable clinical outcome. These findings highlight the importance of mTOR regulated metabolic processes for immune cell functions and argue for implementation of IL-15 in adoptive NK cell cancer therapy. Freshly isolated NK cells from 6 donors were activated with IL-2 or IL-15 for 48 hours, followed by cytokine withdrawal for 24 hours, resulting in four RNA samples per donor. From each sample, both the cytosolic as well as the polysomal fraction were collected. Donor 3 contains activation and post withdrawal data from two different donors due to poor RNA-quality obtained for some samples which did not allow for processing of the complete set of 6 donors (resulting in a total of 40 samples).

Dataset Information

Proliferation conditions promote intrinsic changes in NK Cells for an IL-10 response

Publications

Proliferation conditions promote intrinsic changes in NK cells for an IL-10 response.

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