Dataset Information

TGF? Imprinting During Activation Promotes Natural Killer Cell Cytokine Hypersecretion.

ABSTRACT: Transforming growth factor-beta (TGF?) is a potent immunosuppressive cytokine that inhibits the anti-tumor responses of NK cells and T cells. However, the stimulation of natural killer (NK) cells with pro-inflammatory cytokines decreases NK cell sensitivity to TGF?. Herein, we sought to determine if TGF? imprinting (TGF?i) during NK cell activation and expansion would decrease NK cell sensitivity to TGF? suppression. To this end, we demonstrate that the activation of NK cells during chronic IL-2 stimulation and TGF?i potently induces NK cell hypersecretion of interferon-gamma (IFN?) and tumor necrosis factor-alpha (TNF?) in response to tumor targets which persists for at least one month in vitro after the removal of TGF?. TGF?i NK cell cytokine hypersecretion is induced following both cytokine and tumor activation. Further, TGF?i NK cells have a marked suppression of SMAD3 and T-bet which is associated with altered chromatin accessibility. In contrast to their heightened cytokine secretion, TGF?i NK cells downregulate several activating receptors, granzyme and perforin, and upregulate TRAIL, leading to cell-line-specific alterations in cytotoxicity. These findings may impact our understanding of how TGF? affects NK cell development and anti-tumor function.

SUBMITTER: Foltz JA

PROVIDER: S-EPMC6267005 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

TGFβ Imprinting During Activation Promotes Natural Killer Cell Cytokine Hypersecretion.

Foltz Jennifer A JA Moseman Jena E JE Thakkar Aarohi A Chakravarti Nitin N Lee Dean A DA

Cancers 20181105 11

Transforming growth factor-beta (TGFβ) is a potent immunosuppressive cytokine that inhibits the anti-tumor responses of NK cells and T cells. However, the stimulation of natural killer (NK) cells with pro-inflammatory cytokines decreases NK cell sensitivity to TGFβ. Herein, we sought to determine if TGFβ imprinting (TGFβi) during NK cell activation and expansion would decrease NK cell sensitivity to TGFβ suppression. To this end, we demonstrate that the activation of NK cells during chronic IL-2 ...[more]

PMID: 30400618

Similar Datasets

Project description:Recent reports suggest that Natural Killer (NK) cells may modulate pathogenesis of primary HIV-1 infection. However, HIV dysregulates NK-cell responses. We dissected this bi-directional relationship to understand how HIV impacts NK-cell responses during primary HIV-1 infection.Paired samples from 41 high-risk, initially HIV-uninfected CAPRISA004 participants were analysed prior to HIV acquisition, and during viraemic primary HIV-1 infection. At the time of sampling post-infection five women were seronegative, 11 women were serodiscordant, and 25 women were seropositive by HIV-1 rapid immunoassay. Flow cytometry was used to measure NK and T-cell activation, NK-cell receptor expression, cytotoxic and cytokine-secretory functions, and trafficking marker expression (CCR7, ?(4)?(7)). Non-parametric statistical tests were used. Both NK cells and T-cells were significantly activated following HIV acquisition (p?=?0.03 and p<0.0001, respectively), but correlation between NK-cell and T-cell activation was uncoupled following infection (pre-infection r?=?0.68;p<0.0001; post-infection, during primary infection r?=?0.074;p?=?0.09). Nonetheless, during primary infection NK-cell and T-cell activation correlated with HIV viral load (r?=?0.32'p?=?0.04 and r?=?0.35;p?=?0.02, respectively). The frequency of Killer Immunoglobulin-like Receptor-expressing (KIR(pos)) NK cells increased following HIV acquisition (p?=?0.006), and KIR(pos) NK cells were less activated than KIR(neg) NK cells amongst individuals sampled while seronegative or serodiscordant (p?=?0.001;p<0.0001 respectively). During HIV-1 infection, cytotoxic NK cell responses evaluated after IL-2 stimulation alone, or after co-culture with 721 cells, were impaired (p?=?0.006 and p?=?0.002, respectively). However, NK-cell IFN-y secretory function was not significantly altered. The frequency of CCR7+ NK cells was elevated during primary infection, particularly at early time-points (p<0.0001).Analyses of immune cells before and after HIV infection revealed an increase in both NK-cell activation and KIR expression, but reduced cytotoxicity during acute infection. The increase in frequency of NK cells able to traffic to lymph nodes following HIV infection suggests that these cells may play a role in events in secondary lymphoid tissue.

Dataset Information

TGF? Imprinting During Activation Promotes Natural Killer Cell Cytokine Hypersecretion.

Publications

TGFβ Imprinting During Activation Promotes Natural Killer Cell Cytokine Hypersecretion.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets