title: Ndfip1 restricts Th17 cell potency by limiting lineage stability and proinflammatory cytokine production.
abstract: While Th17 cells can protect against colonization by pathogenic organisms, they also have the potential to become pathogenic and promote autoimmune and inflammatory diseases. Mechanisms that control their pathogenic potential remain poorly understood. Here we show that Ndfip1, a co-activator of the E3 ubiquitin ligase Itch, restricts the frequency and pathogenicity of Th17 cells. Mice lacking Ndfip1 have increased numbers of Th17 cells, and this increase is cell intrinsic. We found that Ndfip1 restricts production of the proinflammatory cytokines in Th17 cells. Increased cytokine production correlated with reduced degradation and accumulation of RORγT. When transferred in vivo, Th17 cells lacking Ndfip1 were more likely to maintain their ability to make IL-17, were more potent proinflammatory cytokine producers, and were powerful inducers of colitis. Together our data support an essential role for Ndfip1 in degrading RORγT and suppressing Th17 lineage stability, proinflammatory cytokine production, and pathogenicity.
authors.affiliation: Medical Scientist Training Program, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Building 421, Philadelphia, PA 19104, USA.|Biomedical graduate Studies, Immunology Graduate Group, 357 Biomedical Research Building II/III, 421 Curie Boulevard, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Awo Akosua
authors.initials: AAK
authors.lastname: Layman
authors.affiliation: The Children's Hospital of Philadelphia, Cell Pathology Division, 3401 Civic Center Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Stephanie
authors.initials: SL
authors.lastname: Sprout
authors.affiliation: The Children's Hospital of Philadelphia, Cell Pathology Division, 3401 Civic Center Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Dylan
authors.initials: D
authors.lastname: Phillips
authors.affiliation: The Children's Hospital of Philadelphia, Cell Pathology Division, 3401 Civic Center Boulevard, Philadelphia, PA 19104, USA.|Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Building 421, Philadelphia, PA 19104, USA.
authors.forename: Paula M
authors.initials: PM
authors.lastname: Oliver
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology*; D005260:Female; D007249:Inflammation / Q000276:immunology*; D018836:Inflammation Mediators / Q000276:immunology; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018345:Mice, Knockout; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D018836:Inflammation Mediators; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C499188:Ndfip1 protein, mouse; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3