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

Journal Article: Journal of ImmunologyYear Published: (2019) Volume Number: 202, Article Number: 684-693


Mann, Elizabeth H.; Gabry š ová, Leona; Pfeffer, Paul E.; O'Garra, Anne; Hawrylowicz, Catherine M.

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.