title: Differential requirement of IKK2 for CYLD-dependent representation of thymic and peripheral T-cell populations.
abstract: The cylindromatosis tumor suppressor gene (Cyld) encodes an enzyme (CYLD) with deubiquitinating activity that has been implicated in the regulation of thymocyte selection in an NF-κB-essential-modulator (NEMO)-dependent manner. The main known molecular defects in thymocytes with inactive CYLD (LckCre-Cyld(flx9/flx9) ) are the aberrant hyperactivation of NF-κB and JNK pathways. In order to dissect further the molecular mechanism of CYLD-dependent thymocyte selection and address the role of NF-κB specifically, we generated double mutant mice (LckCre-Cyld(flx9/flx9) -Ikk2(flx/flx) ) in which CYLD was inactivated concomitantly with IKK2 (IκB-kinase 2) in thymocytes. Interestingly, thymic development and NF-κB activity in double mutant mice were fully restored, indicating that an IKK2-dependent function of CYLD that leads to the hyperactivation of the NF-κB pathway is primarily responsible for the defective selection of thymocytes. Intriguingly, we observed a greater reduction of CD4(+)  and CD8(+)  T cells in the periphery of LckCre-Cyld(flx9/flx9) -Ikk2(flx/flx)  mice compared with LckCre-Ikk2(flx/flx)  mice. Collectively, our data establish CYLD as a critical regulator of thymocyte selection in a manner that depends on IKK2 and NF-κB activation. In addition, our data uncover an IKK2-independent role for CYLD in the establishment of physiological T-cell populations in the periphery.
authors: School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors: Ageliki
authors: A
authors: Tsagaratou
authors: Sofia
authors: S
authors: Grammenoudi
authors: George
authors: G
authors: Mosialos
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000074749:Deubiquitinating Enzyme CYLD; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D051550:I-kappa B Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013950:Thymus Gland / Q000276:immunology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C514981:NEMO protein, mouse; D016328:NF-kappa B; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; C511601:CYLD protein, mouse; D000074749:Deubiquitinating Enzyme CYLD; D003546:Cysteine Endopeptidases