title: Ndfip-mediated degradation of Jak1 tunes cytokine signalling to limit expansion of CD4+ effector T cells.
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.
authors.affiliation: Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Claire E
authors.initials: CE
authors.lastname: O'Leary
authors.affiliation: Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Riling
authors.affiliation: Department of Pathology and Laboratory Medicine, Cell Pathology Division, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Spruce
authors.affiliation: Department of Pathology and Laboratory Medicine, Cell Pathology Division, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Ding
authors.affiliation: Progenra Inc, Malvern, Pennsylvania, 19355, USA.
authors.forename: Suresh
authors.identifier: http://orcid.org/0000-0002-1940-772X
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Pathology and Laboratory Medicine, Cell Pathology Division, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Guoping
authors.initials: G
authors.lastname: Deng
authors.affiliation: Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pathology and Laboratory Medicine, Cell Pathology Division, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Steven H
authors.initials: SH
authors.lastname: Seeholzer
authors.affiliation: Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Department of Pathology and Laboratory Medicine, Cell Pathology Division, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Paula M
authors.initials: PM
authors.lastname: Oliver
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003092:Colitis / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D015151:Immunoblotting; D036341:Intercellular Signaling Peptides and Proteins; D053613:Janus Kinase 1 / Q000378:metabolism*; D018655:Lymphocyte Count; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D059748:Proteolysis; D040901:Proteomics / Q000379:methods; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C000610372:NDFIP2 protein, mouse; C499188:Ndfip1 protein, mouse; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1