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

Abstract

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 ...

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