The Class III Kinase Vps34 Promotes T Lymphocyte Survival through Regulating IL-7Rα Surface Expression

IL-7R alpha-mediated signals are essential for naive T lymphocyte survival. Recent studies show that IL-7R alpha is internalized and either recycled to cell surface or degraded. However, how the intracellular process of IL-7R alpha trafficking is regulated is unclear. In this paper, we show that Vps34, the class III PI3K, plays a critical role in proper IL-7R alpha intracellular trafficking. Mice lacking Vps34 in T lymphocytes had a severely reduced T lymphocyte compartment. Vps34-deficient T lymphocytes exhibit increased death and reduced IL-7R alpha surface expression, although three major forms of autophagy remain intact. Intracellular IL-7R alpha in normal T lymphocytes at steady state is trafficked through either early endosome/multivesicular bodies to the late endosome-Golgi for surface expression or to the lysosome for degradation. However, Vps34-deficient T cells have mislocalized intracellular Eea1, HGF-regulated tyrosine kinase substrate, and Vps36 protein levels, the combined consequence of which is the inability to mobilize internalized IL-7R alpha into the retromer pathway for surface display. Our studies reveal that Vps34, though dispensable for autophagy induction, is a critical regulator of naive T cell homeostasis, modulating IL-7R alpha trafficking, signaling, and recycling. The Journal of Immunology, 2011, 187: 5051-5061.