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

Nature Immunology volume 9, pages 1356–1363 (2008)Cite this article

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.

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Figure 1: Phenotypic analysis of Nedd4+/+ and Nedd4−/− cells isolated from thymus, lymph node and spleen.
Figure 2: Fewer Nedd4−/− T cells than Nedd4+/+ T cells express markers characteristic of an effector phenotype.
Figure 3: T cells lacking Nedd4 expand poorly in response to antigen in vivo and do not provide adequate help to B cells.
Figure 4: Fewer Nedd4−/− T cells than Nedd4+/+ T cells produce IL-2.
Figure 5: Nedd4−/− CD4+ T cells express normal amounts of PTEN and have higher expression of Cbl-b.
Figure 6: Nedd4 binds to and promotes the ubiquitination of Cbl-b.
Figure 7: Depletion of Cbl-b restores IL-2 production in Nedd4-depleted CD4+ T cells.

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Acknowledgements

We thank R. Schwartz (National Institute of Allergy and Infectious Diseases) for Cbl-b-deficient mice; M. Shaffer for help with siRNA experiments; and J. Loomis for sorting cells.

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Author notes

  1. Paula M Oliver

    Present address: Present address: Department of Pathology and Laboratory Medicine, University of Pennsylvania and the Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.,

Authors and Affiliations

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

    Baoli Yang, Xiao Cao & Eileen M Sweezer

  2. Children's Hospital of Philadelphia, Philadelphia, 19104, Pennsylvania, USA

    Denise L Gay & Tamara Hala

  3. Howard Hughes Medical Institute and Integrated Department of Immunology, National Jewish Medical and Research Center and University of Colorado Health Sciences Center, Denver, 80206, Colorado, USA

    Megan K L MacLeod, John Kappler, Philippa Marrack & Paula M Oliver

  4. Departments of Medicine and Pharmacology, University of Colorado Health Sciences Center, Denver, 80206, Colorado, USA

    John Kappler

  5. Department of Medicine and Department of Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, Denver, 80206, Colorado, USA

    Philippa Marrack

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Yang, B., Gay, D., MacLeod, M. et al. Nedd4 augments the adaptive immune response by promoting ubiquitin-mediated degradation of Cbl-b in activated T cells. Nat Immunol 9, 1356–1363 (2008). https://doi.org/10.1038/ni.1670

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