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

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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Correspondence to Paula M Oliver.

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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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