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Interleukin-35 impairs human NK cell effector functions and induces their ILC1-like conversion with tissue residency features

ABSTRACT: While Natural Killer (NK) cells are key players in immune defenses against pathogens and cancers, by directly killing dangerous cells and supporting antitumor functions of other immune cells, they progressively get dysfunctional in chronic inflammatory diseases through mechanisms that remain insufficiently understood. NK cell development, survival, activation, and functions are highly regulated by cytokines. Among them, Interleukin 35 (IL-35), a new member of the IL-12 family released during chronic inflammations, plays a role in immune suppression. However, the direct effect of IL-35 on NK cells is still unknown. In this study, we observed that IL-35-exposed human primary NK cells display dampened proliferation and effector functions associated with differential expressions of activating and inhibitory NK receptors. Brief exposure to IL-35 inhibited NK cell activation and ability to secrete pro-inflammatory cytokines and chemokines, while promoting their production of pro-angiogenic factors and TGF-β. Furthermore, prolonged exposure to IL-35 placed NK cells in a functionally hyporesponsive state associated with a TGF-β-dependent conversion into CD9+ CD103+ CD49a+ ILC1-like cells. Single cell RNAseq further confirmed these observations and revealed an ILC1-like heterogeneity associated to the initial NK subpopulation undergoing the conversion. Thus, our findings identify a new role of IL-35 as a driver of NK cell plasticity leading to the acquisition of tissue residency features and weakened effector functions that might play a role in physiopathological contexts and represent an attractive target for future immunotherapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE256137 | GEO | 2025/05/27

REPOSITORIES: GEO

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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).

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Interleukin-35 impairs human NK cell effector functions and induces their ILC1-like conversion with tissue residency features

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