Suchergebnisse

Almost 30 years ago pioneering work by the laboratories of Harald von Boehmer and Susumo Tonegawa provided the first indications that developing thymocytes could assemble a functional TCRβ chain-containing receptor complex, the pre-TCR, before TCRα expression. The discovery and study of the pre-TCR complex revealed paradigms of signaling pathways in control of cell survival and proliferation, and culminated in the recognition of the multifunctional nature of this receptor. As a receptor integrated in a dynamic developmental process, the pre-TCR must be viewed not only in the light of the biological outcomes it promotes, but also in context with those molecular processes that drive its expression in thymocytes. This review article focuses on transcription factors and target genes activated by the pre-TCR to drive its different outcomes. ; Work in CL-R and JA laboratory has been supported by the Ramón y Cajal and I3 Researchers Programs (CL-R), research grants from the Spanish Government (SAF2009-08066, SAF2012-36535 to CL-R; and BFU2008-01070, SAF2011-24268 to JA), Fundació la Marató TV3 (080730, 122530 to CL-R and JA), the Marie Curie International Reintegration Program of the European Union (MCIRG516308 to CL-R), the Spanish Ministry of Health (ISCIII-RETIC RD06/0009-FEDER), and Generalitat de Catalunya (2009SGR601, 2014SGR1153). CL-R is a recipient of the ICREA Acadèmia Award (Generalitat de Catalunya).

Toll-like receptors (TLRs) engage networks of transcriptional regulators to induce genes essential for antimicrobial immunity. We report that NFAT5, previously characterized as an osmostress responsive factor, regulates the expression of multiple TLR-induced genes in macrophages independently of osmotic stress. NFAT5 was essential for the induction of the key antimicrobial gene Nos2 (inducible nitric oxide synthase [iNOS]) in response to low and high doses of TLR agonists but is required for Tnf and Il6 mainly under mild stimulatory conditions, indicating that NFAT5 could regulate specific gene patterns depending on pathogen burden intensity. NFAT5 exhibited two modes of association with target genes, as it was constitutively bound to Tnf and other genes regardless of TLR stimulation, whereas its recruitment to Nos2 or Il6 required TLR activation. Further analysis revealed that TLR-induced recruitment of NFAT5 to Nos2 was dependent on inhibitor of κB kinase (IKK) β activity and de novo protein synthesis, and was sensitive to histone deacetylases. In vivo, NFAT5 was necessary for effective immunity against Leishmania major, a parasite whose clearance requires TLRs and iNOS expression in macrophages. These findings identify NFAT5 as a novel regulator of mammalian anti-pathogen responses. ; C. López-Rodríguez was supported by the Ramón y Cajal and I3 Researchers Programmes and grants from the Spanish Government (SAF2006-04913 and SAF2009-08066) and European Union (MCIRG516308). J. Aramburu was supported by grants from the Spanish Government (BFU2008-01070 and SAF2011-24268), and Distinció de la Generalitat de Catalunya per a la Promoció de la Recerca Universitària. Research in the laboratories of C. López-Rodríguez and J. Aramburu is also supported by Fundació la Marató TV3 (030230/31, 080730), Spanish Ministry of Health (ISCIII-RETIC RD06/0009-FEDER), and Generalitat de Catalunya (2009 SGR 601). M. Buxadé was supported by a Beatriu de Pinós postdoctoral contract from Generalitat de Catalunya. S. Iborra was supported by a Sara Borrell postdoctoral contract from the Ministry of Health of Spain. J. Minguillón and R. Berga-Bolaños were supported by predoctoral fellowships from the Spanish Government.