title: NFAT5 induction by the pre-T-cell receptor serves as a selective survival signal in T-lymphocyte development.
abstract: The Rel-like transcription factors nuclear factor kappa B (NF-κB) and the calcineurin-dependent nuclear factor of activated T cells (NFATc) control specific points of thymocyte maturation. Thymocytes also express a distinct member of the Rel family, the calcineurin-independent, osmostress response regulator NFAT5. Here we show that IKKβ regulates the expression of NFAT5 in thymocytes, which in turn contributes to the survival of T-cell receptor αβ thymocytes and the transition from the β-selection checkpoint to the double-positive stage in an osmostress-independent manner. NFAT5-deficient thymocytes had normal expression and proximal signaling of the pre-T-cell receptor but exhibited a partial defect in β-chain allelic exclusion and increased apoptosis. Further analysis showed that NFAT5 regulated the expression of the prosurvival factors A1 and Bcl2 and attenuated the proapoptotic p53/Noxa axis. These findings position NFAT5 as a target of the IKKβ/NF-κB pathway in thymocytes and as a downstream effector of the prosurvival role of the pre-T-cell receptor.
authors.affiliation: Immunology Unit, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Berga-Bolaños
authors.forename: Maria
authors.initials: M
authors.lastname: Alberdi
authors.forename: Maria
authors.initials: M
authors.lastname: Buxadé
authors.forename: José
authors.initials: J
authors.lastname: Aramburu
authors.forename: Cristina
authors.initials: C
authors.lastname: López-Rodríguez
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D018507:Gene Expression Regulation, Developmental / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D060168:Thymocytes / Q000166:cytology / Q000276:immunology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D008562:Membrane Glycoproteins; D050778:NFATC Transcription Factors; C408009:Pmaip1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016159:Tumor Suppressor Protein p53; C090377:pre-T cell receptor alpha
keywords: T-cell development; gene expression
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