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J Immunol. 2014 Oct 1;193(7):3322-31. doi: 10.4049/jimmunol.1400775. Epub 2014 Aug 29.

IL-21 is a central memory T cell-associated cytokine that inhibits the generation of pathogenic Th1/17 effector cells.

Author information

1
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;
2
Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi," 20122 Milan, Italy;
3
Deutsches Rheumaforschungszentrum, 10117 Berlin, Germany; Charité Research Centre for Immunosciences, 10115 Berlin, Germany;
4
Department of Otorhinolaryngology, Head and Neck Surgery, Charité University Medical School, Campus Charité Mitte, 10117 Berlin, Germany;
5
Deutsches Rheumaforschungszentrum, 10117 Berlin, Germany;
6
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.
7
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.
8
Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi," 20122 Milan, Italy; geginat@ingm.org.

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.

PMID:
25172491
DOI:
10.4049/jimmunol.1400775
[Indexed for MEDLINE]
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