Article abstract
Nature Immunology 9, 1356 - 1363 (2008)
Published online: 19 October 2008 | doi:10.1038/ni.1670
Nedd4 augments the adaptive immune response by promoting ubiquitin-mediated degradation of Cbl-b in activated T cells
Baoli Yang1, Denise L Gay2, Megan K L MacLeod3, Xiao Cao1, Tamara Hala2, Eileen M Sweezer1, John Kappler3,4, Philippa Marrack3,5 & Paula M Oliver3,6
Abstract
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.
- Department of Obstetrics and Gynecology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
- Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
- Howard Hughes Medical Institute and Integrated Department of Immunology, National Jewish Medical and Research Center and University of Colorado Health Sciences Center, Denver, Colorado 80206, USA.
- Departments of Medicine and Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado 80206, USA.
- Department of Medicine and Department of Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, Denver, Colorado 80206, USA.
- Present address: Department of Pathology and Laboratory Medicine, University of Pennsylvania and the Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
Correspondence to: Paula M Oliver3,6 e-mail: paulao@mail.med.upenn.edu
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