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

Maintenance of T cells is determined by their survival capacity, which is regulated by Bcl‐2 proteins. Cytokines signalling through the common gamma chains such as IL‐2, IL‐7 and IL‐15 are important for T‐cell survival but how these cytokines determine the expression of Bcl‐2‐family proteins is not clear. We report signalling events of cytokines that regulate expression of two key Bcl‐2 proteins, pro‐apoptotic Bim and anti‐apoptotic Mcl‐1, in resting C57BL/6 mouse T cells. IL‐2, IL‐7 and IL‐15 inhibited apoptosis but paradoxically induced the expression of Bim, countered by concomitant induction of Mcl‐1. Bim induction by IL‐15 was found at the mRNA and protein levels and depended on both JAK/STAT and PI3K signals. A new STAT5‐binding site was identified in the Bim promoter, which was occupied by STAT5 upon IL‐15 stimulation. Although it also depended on JAK/STAT‐ and PI3K signalling, Mcl‐1 regulation was independent of Mcl‐1 mRNA levels and of regulation of protein stability, suggesting translational regulation. Concurrent CD3 signals inhibited some of the IL‐7 effect but not the IL‐15 effect on Bcl‐2 proteins. The data suggest that cytokines induce Bim and prime T cells for apoptosis, but also inhibit apoptosis by stabilising Mcl‐1. Later downregulation of short‐lived Mcl‐1 may induce efficient, Bim‐dependent apoptosis.