Increased Antitumor Effects Using IL-2 with Anti–TGF-β Reveals Competition between Mouse NK and CD8 T Cells

Bouchlaka, Myriam N.; Sckisel, Gail D.; Sungur, Can M.; Chen, Mingyi; Murphy, William J.

doi:10.4049/jimmunol.1400034

Cited by 37 publications

(48 citation statements)

References 53 publications

(75 reference statements)

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“…3C). Thus, in agreement with previous studies showing a greater expansion of NK cells in the absence of CD8 T cells (46,47), we have shown in the present study that precise timing of CD8 + cell depletion at the second cycle of stimulation is decisive for NK cell expansion. Finally, such punctual CD8 + cell depletion offers a new opportunity in restoring NK cell responsiveness.…”

Section: Cd44 + Cd8 + Cells Are Implicated In Nk Cell Hyporesponsivenesssupporting

confidence: 94%

Emergence of NK Cell Hyporesponsiveness after Two IL-15 Stimulation Cycles

Frutoso

Morisseau

Tamzalit

et al. 2018

The Journal of Immunology

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IL-15 is a cytokine playing a crucial role in the function of immune cells, including NK and CD8 T cells. In this study, we demonstrated that in vivo, in mice, IL-15-prestimulated NK cells were no longer able to respond to a second cycle of IL-15 stimulation. This was illustrated by defects in cell maturation, proliferation, and activation, seemingly linked to the environment surrounding NK cells but not related to the presence of CD4 regulatory T cells, TGF-β, or IL-10. Moreover, NK cells from immunodeficient mice could respond to two cycles of IL-15 stimulation, whereas an adoptive transfer of CD44CD8 cells impaired their responsiveness to the second cycle. Conversely, in immunocompetent mice, NK cell responsiveness to a second IL-15 stimulation was restored by the depletion of CD8 cells. These biological findings refine our understanding of the complex mode of action of NK cells in vivo, and they should be taken into consideration for IL-15-based therapy.

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Section: Cd44 + Cd8 + Cells Are Implicated In Nk Cell Hyporesponsivenesssupporting

confidence: 94%

Emergence of NK Cell Hyporesponsiveness after Two IL-15 Stimulation Cycles

Frutoso

Morisseau

Tamzalit

et al. 2018

The Journal of Immunology

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“…10 However, the role of host U-NKs in alloBMT has been unclear. Because of the importance of NKs in the protection against virus pathology and the regulation of T-cell responses, 11 we were interested in analyzing the impact of the host-NK subsets on the engraftment of alloBMCs and whether differential functions were observed. The unique cytokine profiles observed after infection allows us to hypothesize that U-NKs can have a beneficial effect on donor reconstitution after alloBMCs and can possibly be useful in the application of NK-based therapy to improve outcomes in clinical BMT.…”

Section: Introductionmentioning

confidence: 99%

Mouse host unlicensed NK cells promote donor allogeneic bone marrow engraftment

Sun

Murphy

2016

Blood

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“…There was also no competitive advantage given to the Cish −/− CD8 + T cells ( Figure 3D). A previous study showed that depletion of CD8 T cells allowed more room for NK cells to expand, however they also showed that in WT mice that this CD8 depletion alone was not enough to encourage NK cell expansion (30). We hypothesized that the absence of CIS would enhance NK cell sensitivity to the unused IL-15 generated from the absence of CD8 T cells, thus breaking NK cell homeostasis.…”

Section: Il-15 Availability Is a Limiting Factor For The Homeostatic mentioning

confidence: 88%

NK Cell Priming From Endogenous Homeostatic Signals Is Modulated by CIS

et al. 2020

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Natural killer (NK) cell activation is controlled by a balance of activating and inhibitory signals and cytokines such as IL-15. We previously identified cytokine-inducible SH2-containing protein (CIS) as a negative regulator of IL-15 signaling in NK cells under inflammatory conditions. While the functional effect of Cish-deficiency in NK cells was obvious by their increased anti-tumor immunity and hyper-proliferative response to IL-15, it remained unclear how CIS regulates NK cell biology in steady-state. Here, we investigated the role of CIS in the homeostatic maintenance of NK cells and found CIS-ablation promoted terminal differentiation of NK cells and increased turnover, suggesting that under steady-state conditions, CIS plays a role in maintaining IL-15 driven regulation of NK cells in vivo. However, hyper-responsiveness to IL-15 did not manifest in NK cell accumulation, even when the essential NK cell apoptosis mediator, Bcl2l11 (BIM) was deleted in addition to Cish. Instead, loss of CIS conferred a lower activation threshold, evidenced by augmented functionality on a per cell basis both in vitro and in vivo without prior priming. We conclude that Cish regulates IL-15 signaling in NK cells in vivo, and through the rewiring of several activation pathways leads to a reduction in activation threshold, decreasing the requirement for priming and improving NK cell anti-tumor function. Furthermore, this study highlights the tight regulation of NK cell homeostasis by several pathways which prevent NK cell accumulation when IL-15 signaling and intrinsic apoptosis are dysregulated.

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Increased Antitumor Effects Using IL-2 with Anti–TGF-β Reveals Competition between Mouse NK and CD8 T Cells

Cited by 37 publications

References 53 publications

Emergence of NK Cell Hyporesponsiveness after Two IL-15 Stimulation Cycles

Emergence of NK Cell Hyporesponsiveness after Two IL-15 Stimulation Cycles

Mouse host unlicensed NK cells promote donor allogeneic bone marrow engraftment

NK Cell Priming From Endogenous Homeostatic Signals Is Modulated by CIS

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