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Nat Commun. 2016 Apr 18;7:11226. doi: 10.1038/ncomms11226.

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

Author information

1
Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
2
Department of Pathology and Laboratory Medicine, Cell Pathology Division, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
3
Progenra Inc, Malvern, Pennsylvania, 19355, USA.
4
Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.

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.

PMID:
27088444
PMCID:
PMC4837450
DOI:
10.1038/ncomms11226
[Indexed for MEDLINE]
Free PMC Article

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