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

Claire E. O’Leary, Christopher R. Riling, Lynn A. Spruce, Hua Ding, Suresh Kumar, Guoping Deng, Yuhong Liu, Steven H. Seeholzer and Paula M. Oliver ()
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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

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11226

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