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High-dose IL-2 skews a glucocorticoid-driven IL-17+IL-10+ memory CD4+ T cell response towards a single IL-10-producing phenotype

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Title: High-dose IL-2 skews a glucocorticoid-driven IL-17+IL-10+ memory CD4+ T cell response towards a single IL-10-producing phenotype
Authors: Mann, EH
Gabryšová, L
Pfeffer, PE
O'Garra, A
Hawrylowicz, CM
Item Type: Journal Article
Abstract: Glucocorticoids are known to increase production of the anti-inflammatory cytokine IL-10, and this action is associated with their clinical efficacy in asthmatics. However, glucocorticoids also enhance the synthesis of IL-17A by PBMCs, which, in excess, is associated with increased asthma severity and glucocorticoid-refractory disease. In this study, we show that the glucocorticoid dexamethasone significantly increased IL-10 production by human memory CD4+ T cells from healthy donors, as assessed by intracellular cytokine staining. In addition, dexamethasone increased production of IL-17A, IL-17F, and IL-22, with the most striking enhancement in cells coproducing Th17-associated cytokines together with IL-10. Of note, an increase in IFN-γ+IL-10+ cells was also observed despite overall downregulation of IFN-γ production. These dexamethasone-driven IL-10+ cells, and predominantly the IL-17+IL-10+ double-producing cells, were markedly refractory to the inhibitory effect of dexamethasone on proliferation and IL-2Rα expression, which facilitated their preferential IL-2-dependent expansion. Although lower concentrations of exogenous IL-2 promoted IL-10+ cells coproducing proinflammatory cytokines, higher IL-2 doses, both alone and in combination with dexamethasone, increased the proportion of single IL-10+ T cells. Thus, glucocorticoid-induced IL-10 is only accompanied by an increase of IL-17 in a low IL-2 setting, which is, nevertheless, likely to be protective owing to the induction of regulatory IL-17+IL-10+-coproducing cells. These findings open new avenues of investigation with respect to the role of IL-2 in glucocorticoid responsiveness that have potential implications for optimizing the benefit/risk ratio of glucocorticoids in the clinic.
Issue Date: 31-Dec-2018
Date of Acceptance: 26-Oct-2018
URI: http://hdl.handle.net/10044/1/66150
DOI: https://dx.doi.org/10.4049/jimmunol.1800697
ISSN: 1550-6606
Publisher: American Association of Immunologists
Start Page: 684
End Page: 693
Journal / Book Title: Journal of Immunology
Volume: 202
Issue: 3
Copyright Statement: © 2019 The Authors This article is distributed under the terms of the CC BY 4.0 Unported license (https://creativecommons.org/licenses/by/4.0/)
Keywords: 1107 Immunology
Publication Status: Published
Conference Place: United States
Online Publication Date: 2019-01-22
Appears in Collections:National Heart and Lung Institute