title: NKT sublineage specification and survival requires the ubiquitin-modifying enzyme TNFAIP3/A20.
abstract: Natural killer T (NKT) cells are innate lymphocytes that differentiate into NKT1, NKT2, and NKT17 sublineages during development. However, the signaling events that control NKT sublineage specification and differentiation remain poorly understood. Here, we demonstrate that the ubiquitin-modifying enzyme TNFAIP3/A20, an upstream regulator of T cell receptor (TCR) signaling in T cells, is an essential cell-intrinsic regulator of NKT differentiation. A20 is differentially expressed during NKT cell development, regulates NKT cell maturation, and specifically controls the differentiation and survival of NKT1 and NKT2, but not NKT17, sublineages. Remaining A20-deficient NKT1 and NKT2 thymocytes are hyperactivated in vivo and secrete elevated levels of Th1 and Th2 cytokines after TCR ligation in vitro. Defective NKT development was restored by compound deficiency of MALT1, a key downstream component of TCR signaling in T cells. These findings therefore show that negative regulation of TCR signaling during NKT development controls the differentiation and survival of NKT1 and NKT2 cells.
authors.affiliation: Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center, 9052 Ghent, Belgium Department of Rheumatology, Ghent University, Ghent University Hospital, 9000 Ghent, Belgium Michael.Drennan@ugent.be Dirk.Elewaut@ugent.be.
authors.forename: Michael B
authors.identifier: 0000-0001-9832-1707
authors.initials: MB
authors.lastname: Drennan
authors.affiliation: Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center, 9052 Ghent, Belgium Department of Rheumatology, Ghent University, Ghent University Hospital, 9000 Ghent, Belgium.
authors.forename: Srinath
authors.identifier: 0000-0003-3979-4824
authors.initials: S
authors.lastname: Govindarajan
authors.affiliation: Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center, 9052 Ghent, Belgium Department of Rheumatology, Ghent University, Ghent University Hospital, 9000 Ghent, Belgium.
authors.forename: Eveline
authors.initials: E
authors.lastname: Verheugen
authors.affiliation: Unit Immunoregulation and Mucosal Immunology, VIB Inflammation Research Center, 9052 Ghent, Belgium Department of Respiratory Medicine, Ghent University, 9000 Ghent, Belgium.
authors.forename: Jonathan M
authors.identifier: 0000-0002-5967-4857
authors.initials: JM
authors.lastname: Coquet
authors.affiliation: Unit of Molecular Signal Transduction in Inflammation, VIB Inflammation Research Center, 9052 Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium.
authors.forename: Jens
authors.identifier: 0000-0003-2664-3357
authors.initials: J
authors.lastname: Staal
authors.affiliation: Unit of Molecular Signal Transduction in Inflammation, VIB Inflammation Research Center, 9052 Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium.
authors.forename: Conor
authors.identifier: 0000-0002-0865-3044
authors.initials: C
authors.lastname: McGuire
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Faculty of Medicine and Health Sciences, Ghent University, Ghent University Hospital, 9000 Ghent, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Taghon
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Faculty of Medicine and Health Sciences, Ghent University, Ghent University Hospital, 9000 Ghent, Belgium.
authors.forename: Georges
authors.identifier: 0000-0002-1691-5294
authors.initials: G
authors.lastname: Leclercq
authors.affiliation: Unit of Molecular Signal Transduction in Inflammation, VIB Inflammation Research Center, 9052 Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium.
authors.forename: Rudi
authors.identifier: 0000-0002-5704-582X
authors.initials: R
authors.lastname: Beyaert
authors.affiliation: Unit of Molecular Signal Transduction in Inflammation, VIB Inflammation Research Center, 9052 Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium.
authors.forename: Geert
authors.identifier: 0000-0002-8427-4775
authors.initials: G
authors.lastname: van Loo
authors.affiliation: Unit Immunoregulation and Mucosal Immunology, VIB Inflammation Research Center, 9052 Ghent, Belgium Department of Respiratory Medicine, Ghent University, 9000 Ghent, Belgium Department of Pulmonary Medicine, Erasmus MC, 3015 CE Rotterdam, Netherlands.
authors.forename: Bart N
authors.initials: BN
authors.lastname: Lambrecht
authors.affiliation: Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center, 9052 Ghent, Belgium Department of Rheumatology, Ghent University, Ghent University Hospital, 9000 Ghent, Belgium Michael.Drennan@ugent.be Dirk.Elewaut@ugent.be.
authors.forename: Dirk
authors.identifier: 0000-0002-7468-974X
authors.initials: D
authors.lastname: Elewaut
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism; D020169:Caspases / Q000172:deficiency / Q000378:metabolism; D019070:Cell Lineage; D002470:Cell Survival; D019426:Integrases / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D055611:Natural Killer T-Cells / Q000166:cytology* / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000172:deficiency / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3 / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D015704:CD4 Antigens; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D025801:Ubiquitin; C045073:Cre recombinase; D019426:Integrases; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D020169:Caspases; C498509:Malt1 protein, mouse; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; C513261:Tnfaip3 protein, mouse