title: Sustained stimulation and expansion of Tregs by IL2 control autoimmunity without impairing immune responses to infection, vaccination and cancer.
abstract: Interleukin 2 (IL2) is the key cytokine supporting survival and function of regulatory T cells (Tregs). We recently reported that low-dose IL2 safely expands/stimulates Tregs and improves autoimmune conditions in humans. Further development of IL2 in autoimmune diseases will require chronic IL2 administration, which could affect beneficial effector immune responses regulated by Tregs. We used recombinant adeno-associated viral vector (rAAV)-mediated gene transfer to continuously release IL2 in mice and assessed its long-term effects on immune responses. A single rAAV-IL2 injection enabled sustained stimulation and expansion of Tregs without inducing Teff activation and prevented diabetes in NOD mice. After several weeks of IL2 production, mice responded normally to a viral challenge and to vaccination, and had pregnancies with offspring that developed normally. They showed no change in the occurrence and growth of chemically-induced tumors. Altogether, chronic low-dose IL2 treatment does not affect beneficial effector immune responses at doses that prevent autoimmune diabetes.
authors.affiliation: UPMC Université Paris 06, Sorbonne Universités, UMR 7211, Immunology-Immunopathology-Immunotherapy (I3), F-75005 Paris, France; CNRS, UMR 7211, Immunology-Immunopathology-Immunotherapy (I3), F-75005 Paris, France; INSERM, UMR_S 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005 Paris, France; AP-HP, Pitié-Salpêtrière hospital, Clinical Investigation Center in Biotherapy, F-75651 Paris, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Churlaud
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 08036 Barcelona, Spain.
authors.forename: Veronica
authors.initials: V
authors.lastname: Jimenez
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 08036 Barcelona, Spain; Department of Anatomy and Animal Health, School of Veterinary Medicine, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Ruberte
authors.affiliation: UPMC Université Paris 06, Sorbonne Universités, UMR 7211, Immunology-Immunopathology-Immunotherapy (I3), F-75005 Paris, France; CNRS, UMR 7211, Immunology-Immunopathology-Immunotherapy (I3), F-75005 Paris, France; INSERM, UMR_S 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005 Paris, France.
authors.forename: Martin
authors.initials: M
authors.lastname: Amadoudji Zin
authors.affiliation: UPMC Université Paris 06, Sorbonne Universités, UMR 7211, Immunology-Immunopathology-Immunotherapy (I3), F-75005 Paris, France; CNRS, UMR 7211, Immunology-Immunopathology-Immunotherapy (I3), F-75005 Paris, France; INSERM, UMR_S 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005 Paris, France.
authors.forename: Gwladys
authors.initials: G
authors.lastname: Fourcade
authors.affiliation: UPMC Université Paris 06, Sorbonne Universités, UMR 7211, Immunology-Immunopathology-Immunotherapy (I3), F-75005 Paris, France; CNRS, UMR 7211, Immunology-Immunopathology-Immunotherapy (I3), F-75005 Paris, France; INSERM, UMR_S 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005 Paris, France.
authors.forename: Gaelle
authors.initials: G
authors.lastname: Gottrand
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 08036 Barcelona, Spain.
authors.forename: Estefania
authors.initials: E
authors.lastname: Casana
authors.affiliation: Veterinary and Agrochemical Research Center (CODA-CERVA), 1180 Brussels, Belgium.
authors.forename: Benedicte
authors.initials: B
authors.lastname: Lambrecht
authors.affiliation: UPMC Université Paris 06, Sorbonne Universités, UMR 7211, Immunology-Immunopathology-Immunotherapy (I3), F-75005 Paris, France; CNRS, UMR 7211, Immunology-Immunopathology-Immunotherapy (I3), F-75005 Paris, France; INSERM, UMR_S 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005 Paris, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Bellier
authors.affiliation: UPMC Université Paris 06, Sorbonne Universités, UMR 7211, Immunology-Immunopathology-Immunotherapy (I3), F-75005 Paris, France; CNRS, UMR 7211, Immunology-Immunopathology-Immunotherapy (I3), F-75005 Paris, France; INSERM, UMR_S 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005 Paris, France.
authors.forename: Eliane
authors.initials: E
authors.lastname: Piaggio
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 08036 Barcelona, Spain.
authors.forename: Fatima
authors.initials: F
authors.lastname: Bosch
authors.affiliation: UPMC Université Paris 06, Sorbonne Universités, UMR 7211, Immunology-Immunopathology-Immunotherapy (I3), F-75005 Paris, France; CNRS, UMR 7211, Immunology-Immunopathology-Immunotherapy (I3), F-75005 Paris, France; INSERM, UMR_S 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005 Paris, France; AP-HP, Pitié-Salpêtrière hospital, Clinical Investigation Center in Biotherapy, F-75651 Paris, France. Electronic address: david.klatzmann@umpc.fr.
authors.forename: David
authors.initials: D
authors.lastname: Klatzmann
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D018014:Gene Transfer Techniques; D057809:HEK293 Cells; D006801:Humans; D007239:Infections / Q000276:immunology*; D007376:Interleukin-2 / Q000009:adverse effects / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D009369:Neoplasms / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D013997:Time Factors; D014611:Vaccination
chemical_list: D007376:Interleukin-2
keywords: Autoimmunity; Cancer; Infection; Inflammation; Maternal–fetal tolerance