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

Ilko Kastirr, Stefano Maglie, Moira Paroni, Johanna Sophie Alfen, Giulia Nizzoli, Elisa Sugliano, Maria Cristina Crosti, Monica Moro, Bodo Steckel, Svenja Steinfelder, Katharina Stölzel, Chiara Romagnani, Fiorenzo Botti, Flavio Caprioli, Massimilliano Pagani, Sergio Abrignani, Jens Geginat

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)3322-3331
Number of pages10
JournalJournal of Immunology
Volume193
Issue number7
DOIs
Publication statusPublished - Oct 1 2014

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

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