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

Nat Immunol. 2008 Dec;9(12):1356-63. doi: 10.1038/ni.1670. Epub 2008 Oct 19.


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.

MeSH terms

  • Animals
  • CD28 Antigens / immunology
  • CD28 Antigens / metabolism
  • Endosomal Sorting Complexes Required for Transport
  • Flow Cytometry
  • Immunoblotting
  • Immunoprecipitation
  • Lymphocyte Activation / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Nedd4 Ubiquitin Protein Ligases
  • Proto-Oncogene Proteins c-cbl / immunology
  • Proto-Oncogene Proteins c-cbl / metabolism*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • Transplantation Chimera
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / immunology*
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination / immunology*


  • CD28 Antigens
  • Endosomal Sorting Complexes Required for Transport
  • Itch protein, mouse
  • Nedd4 Ubiquitin Protein Ligases
  • Nedd4l protein, mouse
  • Proto-Oncogene Proteins c-cbl
  • Ubiquitin-Protein Ligases