Nedd4 augments the adaptive immune response by promoting ubiquitin-mediated degradation of Cbl-b in activated T cells.
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, Antigens, CD28, Endosomal Sorting Complexes Required for Transport, Flow Cytometry, Immunoblotting, Immunoprecipitation, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Proto-Oncogene Proteins c-cbl, T-Lymphocytes, Transplantation Chimera, Ubiquitin-Protein Ligases, Ubiquitination
Animals, Antigens, CD28, Endosomal Sorting Complexes Required for Transport, Flow Cytometry, Immunoblotting, Immunoprecipitation, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Proto-Oncogene Proteins c-cbl, T-Lymphocytes, Transplantation Chimera, Ubiquitin-Protein Ligases, Ubiquitination
Nat. Immunol.
Date: Dec. 01, 2008
PubMed ID: 18931680
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