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

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

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.

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / metabolism*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Proliferation
  • Cells, Cultured
  • Colitis / genetics
  • Colitis / metabolism
  • Cytokines / metabolism*
  • Female
  • Immunoblotting
  • Intercellular Signaling Peptides and Proteins
  • Janus Kinase 1 / metabolism*
  • Lymphocyte Count
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Proteolysis
  • Proteomics / methods
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction*

Substances

  • Carrier Proteins
  • Cytokines
  • Intercellular Signaling Peptides and Proteins
  • Membrane Proteins
  • NDFIP2 protein, mouse
  • Ndfip1 protein, mouse
  • Jak1 protein, mouse
  • Janus Kinase 1