Exposure to inflammatory cytokines selectively limits GM-CSF production by induced T regulatory cells.
Bottom Line: Understanding processes that can limit this potentially deleterious effect of Treg cells in a therapeutic setting is therefore important.We show that iTreg cells can produce significant amounts of three proinflammatory cytokines (IFN-γ, GM-CSF and TNF-α) upon secondary TCR stimulation.Furthermore, we show that IL-6 and IL-27 individually, or IL-2 and TGF-β in combination, can mediate the selective loss of GM-CSF production by iTreg cells.
Affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK.Show MeSH
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Mentions: We addressed whether the inhibitory effects of IL-6, IL-12, and IL-27 upon cytokine production were a unique feature of iTreg cells, or were common to other CD4+ T cell populations capable of producing IFN-γ, GM-CSF, and TNF-α (Fig. 6). For this comparison, iTreg, Th0, and Th1 cells were generated from naïve Tg4.Foxp3LuciDTR-4 cells and restimulated with splenic APCs and a dose response of MBP peptide. In the absence of exogenous cytokines, iTreg cells produced lower levels of GM-CSF and TNF-α than their Th0 and Th1 counterparts. Levels of IFN-γ were similar between iTreg cells and Th0 cells and, as would be expected, these were lower than those detected from Th1 cells (Fig. 6A–C). Addition of either IL-6 or IL-27 inhibited iTreg-cell production of GM-CSF (Fig. 6F), mirroring their effects seen with APC-free TCR stimulation (in Fig. 5). However, inhibition of GM-CSF was not seen with IL-12. GM-CSF production by iTreg cells and Th0 cells was affected in a similar way by exogenous cytokines (Fig. 6D and F), whereas no clear inhibition of Th1-cell production of GM-CSF was evident (Fig. 6E). The only cytokine to clearly elevate IFN-γ production by iTreg cells was IL-12; IL-27 could not achieve this (Fig. 6C). We conclude that, while there is some overlap in how IL-6, IL-12, and IL-27 influence cytokine production by Th0, Th1, and iTreg cells, each cell-type shows a unique response profile to these cytokines.
Affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK.