Yang B, Gay DL, MacLeod MK, Cao X, Hala T, Sweezer EM, Kappler J, Marrack P, Oliver PM

Department of Obstetrics and Gynecology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.

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

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