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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-γ (IFN-γ), 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE55834 | GEO | 2014/08/05

SECONDARY ACCESSION(S): PRJNA241114

REPOSITORIES: GEO

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Project description:The harnessing of natural killer cells (NK cells) as adoptive anti-cancer therapy relies on sufficient numbers of functional NK cells. The use of autologous peripheral blood mononuclear cells (PBMCs) from respective allogeneic donors to boost NK cell proliferation ex vivo, has shown to be a suitable strategy to obtain high NK cell numbers for clinical applications. However, the mechanisms underlying the effect of PBMCs on NK cell proliferation have not been completely characterized. Thus, in this study, we performed a thorough analysis of the influence of autologous PBMCs on NK cell proliferation. We used irradiated autologous CD56-negative PBMCs stimulated with OKT3 that induced significantly increased expansion of purified CD56+CD3- NK cells, already after 5 days of culture (3.2 mean fold, n= 9) compared to standard cultures with only IL-2 supplement (1.3 mean fold n=90 proliferation, as observed when NK cells were cultured separately from the PBMCs through a permeable membrane. Depletion of B cells had no influence on the enhancement of NK cell proliferation, observing no changes in terms of fold expansion or cytokine profile, exemplified by high levels of TNF-α, IFN-γ, IL-6 and GM-CSF. In contrast the absence of T cells or monocytes reduced dramatically the proliferation of NK cells and abrogated cytokine production. Moreover, we analyzed differences in gene expression between proliferating and non-proliferating NK cells within this co-culture set up, to sought to determine changes in signalling pathways or phenotype related to a high proliferative status. The transcriptome analysis indicated that actively proliferating NK cells developed a differential activation response towards the stimuli provided during the co-culture compared to non-proliferating NK cells. In particular, differences in phenotype, expression of mitogen-activated protein kinases and zinc finger transcription factors could be demonstrated. In summary, our findings give rise to improve ex vivo expansion protocols of NK cells for future clinical applications.

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

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