Nedd4 augments the adaptive immune response by promoting ubiquitin-mediated degradation of Cbl-b in activated T cells

Abstract

The E3 ubiquitin ligases Itch and Nedd4 target similar proteins in vitro. Oliver and colleagues find that unlike hyper-responsive Itch-mutant T cells, Nedd4-deficient T cells are hyporesponsive and contain excess Cbl-b. Nedd4 and Itch are E3 ubiquitin ligases that ubiquitinate similar targets in vitro and thus are thought to function similarly. T cells lacking Itch show spontaneous activation and T helper type 2 polarization. To test whether loss of Nedd4 affects T cells in the same way, we generated Nedd4+/+ and Nedd4−/− fetal liver chimeras. Nedd4−/− T cells developed normally but proliferated less, produced less interleukin 2 and provided inadequate help to B cells. Nedd4−/− T cells contained more of the E3 ubiquitin ligase Cbl-b, and Nedd4 was required for polyubiquitination of Cbl-b induced by CD28 costimulation. Our data demonstrate that Nedd4 promotes the conversion of naive T cells into activated T cells. We propose that Nedd4 and Itch ubiquitinate distinct target proteins in vivo.