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

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Item Type:	Article
Title:	IL-21 is a central memory T cell-associated cytokine that inhibits the generation of pathogenic Th1/17 effector cells
Creators Name:	Kastirr, I., Maglie, S., Paroni, M., Alfen, J.S., Nizzoli, G., Sugliano, E., Crosti, M.C., Moro, M., Steckel, B., Steinfelder, S., Stölzel, K., Romagnani, C., Botti, F., Caprioli, F., Pagani, M., Abrignani, S. and Geginat, J.
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.
Keywords:	Autoimmune Diseases, Cell Differentiation, Immunologic Memory, Interleukin-10, Interleukin-12, Interleukin-6, Interleukins, Nuclear Receptor Subfamily 1 Group F Member 3, T-Box Domain Proteins, Th1 Cells, Th17 Cells, Up-Regulation, Animals, Mice
Source:	Journal of Immunology
ISSN:	0022-1767
Publisher:	American Association of Immunologists
Volume:	193
Number:	7
Page Range:	3322-3331
Date:	1 October 2014
Official Publication:	https://doi.org/10.4049/jimmunol.1400775
PubMed:	View item in PubMed

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