title: Constitutively active Stat5b signaling confers tolerogenic functions to dendritic cells of NOD mice and halts diabetes progression.
abstract: Defects in dendritic cells (DCs) development and function lead to autoimmune disorders. Autoimmune diabetes in humans and NOD mice results from a breakdown of self-tolerance, ending in T cell-mediated β-cell destruction. DCs dysfunction in NOD mice results in part from a defect in the JAK-STAT5 signaling pathway associated with the idd4 susceptibility locus. The involvement of Stat5b in DCs tolerogenic functions remains unknown. We have generated transgenic mice (NOD.CD11cStat5b-CA) expressing a constitutively active form of the Stat5b gene (Stat5b-CA) under control of CD11c promoter. All NOD.CD11cStat5b-CAmice were protected against diabetes. Protection was associated with an increased in the pool and suppressive function of Tregs, a promotion of Th2 and Tc2 immune response and a decreased percentage of CD8+T cells. Splenic DCs of NOD.CD11cStat5b-CAmice acquired a mature phenotype, promoted and induced better conversion of CD4+CD25-Foxp3-T cells into Tregs (CD4+CD25+Foxp3+T cells) than DCs of NOD mice. Stat5b-CA.DC-educated CD4+CD25-T cells delayed diabetes onset whereas Stat5b-CA.DC-educated Tregs blocked ongoing diabetes in 8-10 weeks old NOD recipient mice. Importantly, injection of Stat5b.CA.DC to 8-10-week old NOD mice halted diabetes progression and educated their splenocytes to loose their diabetogenic potential when transferred to NOD.SCID mice. Our work is the first to report that an active form of Stat5b restored DCs tolerogenic functions that re-educated Tregs to re-establish and to sustain long-term protective immune response against diabetes in NOD mice.
authors.affiliation: Department of Pediatric, Immunology Division, Centre de Recherche Clinique CHUS, Faculty of Medicine and Health Sciences, University of Sherbrooke, Canada.
authors.forename: Echarki
authors.initials: E
authors.lastname: Zerif
authors.affiliation: Department of Pediatric, Immunology Division, Centre de Recherche Clinique CHUS, Faculty of Medicine and Health Sciences, University of Sherbrooke, Canada.
authors.forename: Aida
authors.initials: A
authors.lastname: Maalem
authors.affiliation: Department of Pediatric, Immunology Division, Centre de Recherche Clinique CHUS, Faculty of Medicine and Health Sciences, University of Sherbrooke, Canada.
authors.forename: Simon
authors.initials: S
authors.lastname: Gaudreau
authors.affiliation: Department of Pediatric, Immunology Division, Centre de Recherche Clinique CHUS, Faculty of Medicine and Health Sciences, University of Sherbrooke, Canada.
authors.forename: Chantal
authors.initials: C
authors.lastname: Guindi
authors.affiliation: Department of Pediatric, Immunology Division, Centre de Recherche Clinique CHUS, Faculty of Medicine and Health Sciences, University of Sherbrooke, Canada.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ramzan
authors.affiliation: Department of Pediatric, Immunology Division, Centre de Recherche Clinique CHUS, Faculty of Medicine and Health Sciences, University of Sherbrooke, Canada.
authors.forename: Steeve
authors.initials: S
authors.lastname: Véroneau
authors.affiliation: Department of Pediatric, Immunology Division, Centre de Recherche Clinique CHUS, Faculty of Medicine and Health Sciences, University of Sherbrooke, Canada.
authors.forename: Denis
authors.initials: D
authors.lastname: Gris
authors.affiliation: Department of Pediatric, Immunology Division, Centre de Recherche Clinique CHUS, Faculty of Medicine and Health Sciences, University of Sherbrooke, Canada.
authors.forename: Jana
authors.initials: J
authors.lastname: Stankova
authors.affiliation: Department of Pediatric, Immunology Division, Centre de Recherche Clinique CHUS, Faculty of Medicine and Health Sciences, University of Sherbrooke, Canada.
authors.forename: Marek
authors.initials: M
authors.lastname: Rola-Pleszczynski
authors.affiliation: Centre de Recherche-Centre Hospitalier de l'Université de Montréal (CR-CHUM), Montréal, Canada.
authors.forename: Walid
authors.initials: W
authors.lastname: Mourad
authors.affiliation: Department of Biochemistry, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Quebec, J1H 5N4, Canada.
authors.forename: Gilles
authors.initials: G
authors.lastname: Dupuis
authors.affiliation: Department of Pediatric, Immunology Division, Centre de Recherche Clinique CHUS, Faculty of Medicine and Health Sciences, University of Sherbrooke, Canada. Electronic address: Abdelaziz.Amrani@USherbrooke.ca.
authors.forename: Abdelaziz
authors.initials: A
authors.lastname: Amrani
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity; D015415:Biomarkers; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D016130:Immunophenotyping; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D010641:Phenotype; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D017634:Self Tolerance / Q000276:immunology*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D001324:Autoantigens; D015415:Biomarkers; D016207:Cytokines; D050799:STAT5 Transcription Factor