title: IL-21 is a central memory T cell-associated cytokine that inhibits the generation of pathogenic Th1/17 effector cells.
abstract: IL-21 promotes Th17 differentiation, and Th17 cells that upregulate T-bet, IFN-γ, and GM-CSF drive experimental autoimmune diseases in mice. Anti-IL-21 treatment of autoimmune patients is therefore a therapeutic option, but the role of IL-21 in human T cell differentiation is incompletely understood. IL-21 was produced at high levels by human CD4(+) central memory T cells, suggesting that it is associated with early T cell differentiation. Consistently, it was inhibited by forced expression of T-bet or RORC2, the lineage-defining transcription factors of Th1 and Th17 effector cells, respectively. Although IL-21 was efficiently induced by IL-12 in naive CD4(+) T cells, it inhibited the generation of Th1 effector cells in a negative feedback loop. IL-21 was also induced by IL-6 and promoted Th17 differentiation, but it was not absolutely required. Importantly, however, IL-21 promoted IL-10 secretion but inhibited IFN-γ and GM-CSF production in developing Th17 cells, and consequently prevented the generation of polyfunctional Th1/17 effector cells. Moreover, in Th17 memory cells, IL-21 selectively inhibited T-bet upregulation and GM-CSF production. In summary, IL-21 is a central memory T cell-associated cytokine that promotes Th17 differentiation and IL-10 production, but inhibits the generation of potentially pathogenic Th1/17 effector cells. These findings shed new light on the role of IL-21 in T cell differentiation, and have relevant implications for anti-IL-21 therapy of autoimmune diseases.
authors.affiliation: Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi," 20122 Milan, Italy; Deutsches Rheumaforschungszentrum, 10117 Berlin, Germany; Charité Research Centre for Immunosciences, 10115 Berlin, Germany;
authors.forename: Ilko
authors.initials: I
authors.lastname: Kastirr
authors.affiliation: Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi," 20122 Milan, Italy;
authors.forename: Stefano
authors.initials: S
authors.lastname: Maglie
authors.affiliation: Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi," 20122 Milan, Italy;
authors.forename: Moira
authors.initials: M
authors.lastname: Paroni
authors.affiliation: Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi," 20122 Milan, Italy;
authors.forename: Johanna Sophie
authors.initials: JS
authors.lastname: Alfen
authors.affiliation: Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi," 20122 Milan, Italy;
authors.forename: Giulia
authors.initials: G
authors.lastname: Nizzoli
authors.affiliation: Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi," 20122 Milan, Italy;
authors.forename: Elisa
authors.initials: E
authors.lastname: Sugliano
authors.affiliation: Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi," 20122 Milan, Italy;
authors.forename: Maria-Cristina
authors.initials: MC
authors.lastname: Crosti
authors.affiliation: Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi," 20122 Milan, Italy;
authors.forename: Monica
authors.initials: M
authors.lastname: Moro
authors.affiliation: Deutsches Rheumaforschungszentrum, 10117 Berlin, Germany; Charité Research Centre for Immunosciences, 10115 Berlin, Germany;
authors.forename: Bodo
authors.initials: B
authors.lastname: Steckel
authors.affiliation: Deutsches Rheumaforschungszentrum, 10117 Berlin, Germany; Charité Research Centre for Immunosciences, 10115 Berlin, Germany;
authors.forename: Svenja
authors.initials: S
authors.lastname: Steinfelder
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Charité University Medical School, Campus Charité Mitte, 10117 Berlin, Germany;
authors.forename: Katharina
authors.initials: K
authors.lastname: Stölzel
authors.affiliation: Deutsches Rheumaforschungszentrum, 10117 Berlin, Germany;
authors.forename: Chiara
authors.initials: C
authors.lastname: Romagnani
authors.affiliation: Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Universitá di Milano, 20122 Milan, Italy; Unitá Operativa di Chirurgia Generale e d'Urgenza, 20122 Milan, Italy; and.
authors.forename: Fiorenzo
authors.initials: F
authors.lastname: Botti
authors.affiliation: Unitá Operativa di Chirurgia Generale e d'Urgenza, 20122 Milan, Italy; and Unitá Operativa di Gastroenterologia 2, Fondazione IRCCS Cá Granda, Ospedale Policlinico di Milano, 20122 Milan, Italy.
authors.forename: Flavio
authors.initials: F
authors.lastname: Caprioli
authors.affiliation: Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi," 20122 Milan, Italy;
authors.forename: Massimilliano
authors.initials: M
authors.lastname: Pagani
authors.affiliation: Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi," 20122 Milan, Italy;
authors.forename: Sergio
authors.initials: S
authors.lastname: Abrignani
authors.affiliation: Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi," 20122 Milan, Italy; geginat@ingm.org.
authors.forename: Jens
authors.initials: J
authors.lastname: Geginat
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D002454:Cell Differentiation / Q000276:immunology*; D005260:Female; D006801:Humans; D007156:Immunologic Memory; D016753:Interleukin-10 / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D007378:Interleukins / Q000276:immunology*; D008297:Male; D051379:Mice; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000276:immunology; D020825:T-Box Domain Proteins / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology; D015854:Up-Regulation / Q000276:immunology; D000098815:T-bet Transcription Factor; D000098546:Interleukin-21
chemical_list: C508609:IL10 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D007378:Interleukins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D016753:Interleukin-10; D018664:Interleukin-12; D000098546:Interleukin-21