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Ndfip-mediated degradation of Jak1 tunes cytokine signalling to limit expansion of CD4+ effector T cells

Author

Listed:
  • Claire E. O’Leary

    (Perelman School of Medicine, University of Pennsylvania)

  • Christopher R. Riling

    (Perelman School of Medicine, University of Pennsylvania)

  • Lynn A. Spruce

    (The Children’s Hospital of Philadelphia)

  • Hua Ding

    (The Children’s Hospital of Philadelphia)

  • Suresh Kumar

    (Progenra Inc)

  • Guoping Deng

    (The Children’s Hospital of Philadelphia)

  • Yuhong Liu

    (The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA)

  • Steven H. Seeholzer

    (The Children’s Hospital of Philadelphia)

  • Paula M. Oliver

    (Perelman School of Medicine, University of Pennsylvania
    The Children’s Hospital of Philadelphia)

Abstract

Nedd4 family E3 ubiquitin ligases have been shown to restrict T-cell function and impact T-cell differentiation. We show here that Ndfip1 and Ndfip2, activators of Nedd4 family ligases, together limit accumulation and function of effector CD4+ T cells. Using a three-part proteomics approach in primary T cells, we identify stabilization of Jak1 in Ndfip1/2-deficient T cells stimulated through the TCR. Jak1 degradation is aborted in activated T cells that lack Ndfips. In wild-type cells, Jak1 degradation lessens CD4+ cell sensitivity to cytokines during TCR stimulation, while in Ndfip-deficient cells cytokine responsiveness persists, promoting increased expansion and survival of pathogenic effector T cells. Thus, Ndfip1/Ndfip2 regulate the cross talk between the T-cell receptor and cytokine signalling pathways to limit inappropriate T-cell responses.

Suggested Citation

  • Claire E. O’Leary & Christopher R. Riling & Lynn A. Spruce & Hua Ding & Suresh Kumar & Guoping Deng & Yuhong Liu & Steven H. Seeholzer & Paula M. Oliver, 2016. "Ndfip-mediated degradation of Jak1 tunes cytokine signalling to limit expansion of CD4+ effector T cells," Nature Communications, Nature, vol. 7(1), pages 1-14, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11226
    DOI: 10.1038/ncomms11226
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