title: TLR Ligand-Induced Type I IFNs Affect Thymopoiesis.
abstract: The interactions between TLRs and their ligands have profound immune modulation properties. Attention has focused mostly on the impact of TLR ligands on peripheral innate and adaptive immunity during viral infections, whereas little impact of TLR activation has been shown on thymic development. Here we show that treatment of murine fetal thymic organ cultures (FTOCs) with TLR3 or TLR7 ligands induced rapid expression of IFN-alpha and -beta mRNA, hallmarks of acute and chronic viral infections. This resulted in an early developmental blockade, increased frequencies of apoptotic cells, and decreased proliferation of thymocytes, which led to an immediate decrease in cellularity. FTOCs infected with vesicular stomatitis virus, known to act through TLR7, were similarly affected. Down-regulation of IL-7R alpha-chain expression, together with an increased expression of suppressor of cytokine signaling-1 and a concomitant decreased expression of the transcriptional regulator growth factor independence 1 were observed in TLR ligands or IFN-treated FTOCs. This indicates a role for these pathways in the observed changes in thymocyte development. Taken together, our data demonstrate that TLR activation and ensuing type I IFN production exert a deleterious effect on T cell development. Because TLR ligands are widely used as vaccine adjuvants, their immunomodulatory actions mediated mainly by IFN-alpha suggested by our results should be taken in consideration.
authors.affiliation: Laboratoire d'Immunologie, Immunologie Humaine, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Hôpital Saint-Luc, Montréal, Québec, Canada.
authors.forename: Marie-Laurence
authors.initials: ML
authors.lastname: Baron
authors.forename: Dominique
authors.initials: D
authors.lastname: Gauchat
authors.forename: Ross
authors.initials: R
authors.lastname: La Motte-Mohs
authors.forename: Nadia
authors.initials: N
authors.lastname: Kettaf
authors.forename: Ali
authors.initials: A
authors.lastname: Abdallah
authors.forename: Thomas
authors.initials: T
authors.lastname: Michiels
authors.forename: Juan-Carlos
authors.initials: JC
authors.lastname: Zúñiga-Pflücker
authors.forename: Rafick-Pierre
authors.initials: RP
authors.lastname: Sékaly
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D006151:Guanosine / Q000031:analogs & derivatives / Q000494:pharmacology; D007370:Interferon Type I / Q000276:immunology / Q000378:metabolism*; D008024:Ligands; D038041:Lymphopoiesis; D051379:Mice; D008810:Mice, Inbred C57BL; D011070:Poly I-C / Q000494:pharmacology; D018353:Rhabdoviridae Infections / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation; D018116:Vesiculovirus
chemical_list: D016207:Cytokines; D007370:Interferon Type I; D008024:Ligands; D051193:Toll-Like Receptors; D006151:Guanosine; C068562:loxoribine; D011070:Poly I-C