Interleukin 15–mediated survival of natural killer cells is determined by interactions among Bim, Noxa and Mcl-1

Huntington, Nicholas D.; Puthalakath, Hamsa; Gunn, Priscilla; Naik, Edwina; Michalak, Ewa M.; Smyth, Mark J.; Tabarias, H.; Degli-Esposti, Mariapia A.; Dewson, Grant; Willis, Simon N.; Motoyama, Noboru; Huang, David C.S.; Nutt, Stephen L.; Tarlinton, David M.; Strasser, Andreas

doi:10.1038/ni1487

Cited by 235 publications

(254 citation statements)

References 49 publications

Supporting

Mentioning

236

Contrasting

Unclassified

Order By: Relevance

“…IL-15 was found to stabilise Mcl-1 while delaying spontaneous apoptosis in neutrophils [26] as well as in NK cells [27]. However, in NK cells IL-15 has been found to down-regulate the expression of Bim to a small degree depending on Bim regulation by Foxo3 [27]. Regulation of Bim by IL-15 can therefore be very different in different cell types and perhaps situations, suggesting that this has different biological consequences in different cells.…”

Section: Discussionmentioning

confidence: 95%

“…Intriguingly, although IL-15 has also been found to stabilise Mcl-1, this effect of IL-15 appears to be conserved between cell types while the effect on Bim is not. IL-15 was found to stabilise Mcl-1 while delaying spontaneous apoptosis in neutrophils [26] as well as in NK cells [27]. However, in NK cells IL-15 has been found to down-regulate the expression of Bim to a small degree depending on Bim regulation by Foxo3 [27].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

IL‐15 regulates Bcl‐2 family members Bim and Mcl‐1 through JAK/STAT and PI3K/AKT pathways in T cells

2014

View full text Add to dashboard Cite

Maintenance of T cells is determined by their survival capacity, which is regulated by IntroductionDuring maturation and in the mature state, T-cell homeostasis is regulated by two processes: apoptosis and proliferation [1,2]. In resting T cells, apoptosis is largely determined by the Bcl-2 family of proteins, and T-cell survival is regulated by the effect that extrinsic signals have on Bcl-2-family proteins [3]. The main stimuli in the regulation of both proliferation and survival are signals received by common gamma chain cytokines such as IL-7, IL-2 and IL-15, and through the TCR. The main players are similar in the regulation of apoptosis in activated T cells. At the end of the immune response, when the antigen has been cleared, most T cells Correspondence: Dr. Georg Häcker e-mail: georg.haecker@uniklinik-freiburg.de die by apoptosis. Activated T-cell death is probably mostly triggered by the disappearance of cytokines and is also mainly implemented by the Bcl-2 family of proteins, a process also referred to as mitochondrial apoptosis [1,3,4].Of the five established anti-apoptotic Bcl-2 proteins, four have been shown to be involved in the regulation of T-cell survival, namely Bcl-2, Bcl-X L , 5,6]. On the pro-apoptotic side, Bim is the most important trigger of apoptosis [7,8], while weaker activity has also been found for Puma [9,10] and during glucose deprivation for Noxa [11]. These triggers (known as BH3-only proteins) act on Bax and/or Bak, which then implement mitochondrial apoptosis [12].The main players within the apoptotic apparatus are therefore fairly well established. Substantial gaps remain, however, in our understanding how the outside signals are transduced and translated into activation or inhibition of activation of the We previously made the observation that IL-2, IL-7 and IL-15 (all cytokines signalling through the common gamma chain (γ c )), while inhibiting apoptosis in activated T cells, increase rather than decrease the protein levels of pro-apoptotic Bim [16]. In this study, we follow up on that observation and demonstrate that a similar effect is found in resting T cells. During IL-15 stimulation, both phospho-inositol-3-kinase (PI3K) and STAT signalling were necessary for the increase in Bim levels. Bim upregulation was accompanied by increased levels of Bim mRNA. A new STAT5 binding site was identified in the Bim promoter, and binding of STAT5 to this site upon IL-15 stimulation was demonstrated. Mcl-1 was further shown to be upregulated by IL-15, also requiring PI3K and STAT signalling. This suggests that the Bim upregulation is counterbalanced by Mcl-1 and may serve the function of sensitising the cells for quick apoptosis once the survival factor has disappeared. Concurrent CD3 signals also had a varying effect on the induction of Bim or Mcl-1 through γ c -signals, supporting the concept of regulation of Bcl-2 proteins through the concerted action of upstream signal transduction. Results γ c cytokines induce expression of pro-apoptotic Bim while promoting T-cell survivalWe have ...

show abstract

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

IL‐15 regulates Bcl‐2 family members Bim and Mcl‐1 through JAK/STAT and PI3K/AKT pathways in T cells

2014

View full text Add to dashboard Cite

show abstract

“…Stimulation of NK cells with IL-15 induced activation of the PI3K and MAPK pathways with phospho-Erk1/2 being responsible for Bim phosphorylation and degradation, whereas IL-15 mediated activation of the PI3K pathway was required to phosphorylate and inhibit Foxo3a (also called FKHR-L1), a member of the family of Forkhead box class O transcription factors known to induce Bim (Bcl2l11) transcription 21 . The dependency on Bim for NK cell apoptosis is evident by the resistance of Bim À / À NK cells to cell death in the absence of IL-15 and their ability to persist when transferred in IL15 À / À mice 14 . IL-7, IL-15 and IL-2 are known to promote the survival of various T-cell subsets with upregulation of Mcl-1 observed following stimulation with these cytokines and deletion of Mcl1 in differentiated T cells resulting in a significant reduction in their numbers in vivo 22,23 , indicating a key requirement for Mcl-1 in their steady-state survival.…”

mentioning

confidence: 99%

“…Both IL-2 and IL-15 utilize IL-2Rg/b heterodimers to transmit proliferative and survival signals to NK cells and have been shown to induce, enhance or maintain various members of the Bcl-2 family of anti-apoptotic proteins including Bcl-2, Bcl-xL and Mcl-1 (refs [14][15][16][17][18][19][20]. On the flipside, we previously proposed that IL-15 regulates NK cell survival by inhibiting the activation of the BH3-only protein Bim 14 . In this instance, Bim protein levels dramatically increased in NK cells upon removal of IL-15 correlating with accelerated apoptosis.…”

mentioning

confidence: 99%

Innate immunodeficiency following genetic ablation of Mcl1 in natural killer cells

Sathe

Delconte

Souza-Fonseca-Guimarães

et al. 2014

Nat Commun

Self Cite

167

154

View full text Add to dashboard Cite

The cytokine IL-15 is required for natural killer (NK) cell homeostasis; however, the intrinsic mechanism governing this requirement remains unexplored. Here we identify the absolute requirement for myeloid cell leukaemia sequence-1 (Mcl1) in the sustained survival of NK cells in vivo. Mcl1 is highly expressed in NK cells and regulated by IL-15 in a dose-dependent manner via STAT5 phosphorylation and subsequent binding to the 3 0 -UTR of Mcl1. Specific deletion of Mcl1 in NK cells results in the absolute loss of NK cells from all tissues owing to a failure to antagonize pro-apoptotic proteins in the outer mitochondrial membrane. This NK lymphopenia results in mice succumbing to multiorgan melanoma metastases, being permissive to allogeneic transplantation and being resistant to toxic shock following polymicrobial sepsis challenge. These results clearly demonstrate a non-redundant pathway linking IL-15 to Mcl1 in the maintenance of NK cells and innate immune responses in vivo.

show abstract

“…La déplétion des monocytes chez la souris entraîne un rapide déclin de la population NK la plus mature CD11b + CD27 - [21]. L'IL-15 agit via son rôle antiapoptotique : d'une part, elle limite l'expression de Bim, un membre pro-apoptotique de la famille Bcl2 (B-cell lymphoma 2), d'autre part, elle augmente l'expression des membres antiapoptotiques de cette famille Bcl2 [22] et Mcl1 (myeloid cell leukemia protein 1) [23].…”

Section: Facteurs De Survie Et Taux De Renouvellementunclassified

Homéostasie des cellulesnatural killer

et al. 2012

View full text Add to dashboard Cite

Interleukin 15–mediated survival of natural killer cells is determined by interactions among Bim, Noxa and Mcl-1

Cited by 235 publications

References 49 publications

IL‐15 regulates Bcl‐2 family members Bim and Mcl‐1 through JAK/STAT and PI3K/AKT pathways in T cells

IL‐15 regulates Bcl‐2 family members Bim and Mcl‐1 through JAK/STAT and PI3K/AKT pathways in T cells

Innate immunodeficiency following genetic ablation of Mcl1 in natural killer cells

Homéostasie des cellulesnatural killer

Contact Info

Product

Resources

About