IL‐15 modulates the balance between Bcl‐2 and Bim via a Jak3/1‐PI3K‐Akt‐ERK pathway to promote CD8αα⁺ intestinal intraepithelial lymphocyte survival

Abstract

IL-15 is an essential survival factor for CD8αα+ intestinal intraepithelial lymphocytes + iIEL survival by both increasing Bcl-2 levels and dissociating Bim from Bcl-2 through activation of a Jak3-Jak1-PI3K-Akt-ERK1/2 pathway, which differs from a previously reported IL-15-induced survival signal.Keywords: Bcl-2 r Bim r CD8αα + intestinal intraepithelial lymphocytes (iIELs) r IL-15Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionIntestinal intraepithelial lymphocytes (iIELs) are T cells located between the epithelial cells lining the intestinal lumen. In the small intestine of C57BL/6J (B6J) mice, approximately half the iIELs are conventional T cells, while the other half are CD4 − CD8β − CD8α + Correspondence: Dr. Nan-Shih Liao e-mail: mbfelix@imb.sinica.edu.tw (CD8αα + ) cells that consist of 30% TCRαβ + (αβ) cells and 70% TCRγδ + (γδ) cells. CD8αα + iIELs are developmentally and functionally distinct from conventional T cells. Most CD8αα + iIEL precursors go through a thymic stage of development, and complete maturation in the intestine [1][2][3][4]. Functionally, CD8αα + iIELs appear to assume an immune regulatory role in the gut mucosa, as implied by their production of immune suppressive cytokines, such as TGF-β and IL-10, and by their ability to inhibit colitis [5,6]. IL-15 is a pleiotropic cytokine widely expressed with its exclusive high affinity receptor 2306 Yein-Gei Lai et al. Eur. J. Immunol. 2013. 43: 2305-2316 expressed mainly by hematopoietic cells [7][8][9]. IL-15 and IL-15Rα form a complex during synthesis in the ER and exist as transmembrane and soluble forms [10]. The transmembrane IL-15-IL-15Rα complex is "in trans presented" to the IL-15Rβγ on neighboring cells for usage [11]. Fig. 1A and B). Inhibitors of Jak3, PI3K (LY294002), protein kinase B/Akt (Akt) (Akt IV) and MEK (U0126) abolished IL-15's prosurvival, whereas inhibitors of p38 mitogen-activated protein kinase (SB203580) and mammalian target of rapamycin inhibitor (rapamycin) had no effect (Fig. 1B, line graphs). The effective inhibitors diminished IL-15's prosurvival effect in a dose-dependent manner (Supporting Information Fig. 1C). As the αβ and γδ cell composition of CD8αα + iIELs remained the same before and after culturing in medium alone, in IL-15, or in IL-15 plus each inhibitor (Fig. 1B, bar graphs), the IL-15-triggered survival signals are similar in the two subsets at the level of Jak3, PI3K, and ERK1/2 activation. Consistent with the inhibitors' effects on CD8αα + iIEL survival (Fig. 1B), IL-15 induced phosphorylation of Jak1, Akt, and ERK1/2 ( Fig. 1C) with delayed kinetics for ERK1/2 phosphorylation. Moreover, the Jak3 inhibitor abolished Jak1 and Akt phosphorylation, while the PI3K inhibitor did not abolish Jak1 phosphorylation (Fig. 1D). On the other hand, PI3K and Akt inhibitors abolished Akt as well as ERK1/2 phosphorylation, whereas the MEK inhibitor abolished ERK1/2 but not Akt phosphorylation (Fig. 1E). Taken together, IL-15 trigger...

Activation and Function of iNKT and MAIT Cells

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

“…A recent study found a converse regulation of Bcl-2-family proteins by either IL-7 or TCR signals, where IL-7, for instance, upregulated Bcl-2 mRNA but this upregulation was dominantly inhibited by concurrent CD3 stimulation [6]. In intestinal intraepithelial CD8αα + T cells, IL-15 was also found to upregulate Mcl-1 and Bcl-2 [15].…”

Conserved IL-2Rγc Signaling Mediates Lymphopoiesis in Zebrafish

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