Differential regulation of the IL-17 receptor by γc cytokines: Inhibitory signaling by the phosphatidylinositol 3-kinase pathway

The γc-family cytokine IL-2 activates signaling events that contribute to cell survival and proliferation, the best-studied of which are the STAT-5 and phosphatidylinositol 3-kinase (PI3K) pathways. The starting point of this study was to define genes regulated by the IL-2R-mediated PI3K pathway in T cells. Accordingly, we used an erythropoietin (EPO) receptor chimeric receptor system in which IL-2-dependent HT-2 T cells expressed a mutant EPO-IL-2Rβ construct where Tyr-338 is mutated to Phe. Cells expressing this mutant IL-2Rβ chain fail to induce phosphorylation of PI3K-p85α/β or activate Akt, but mediate normal IL-2-dependent proliferation and activation of JAK1 and STAT-5A/B. Microarray analyses revealed differential regulation of numerous genes compared with cells expressing a wild-type IL-2Rβ, including up-regulation of the IL-17 receptor subunit IL-17RA. Blockade of the PI3K pathway but not p70^S6K led to up-regulation of IL-17RA, and constitutive Akt activation was associated with suppressed IL-17RA expression. Moreover, similar to the mutant EPO-IL-2R chimera, IL-15 and IL-21 induced IL-17RA preferentially compared with IL-2, and IL-2 but not IL-15 or IL-21 mediated prolonged activation of the PI3K p85 regulatory subunit. Thus, there are intrinsic signaling differences between IL-2 and IL-15 that can be attributed to differences in activation of the PI3K pathway.