Abstract
Although the differentiation of CD4+T cells is widely studied, the mechanisms of antigen-presenting cell-dependent T-cell modulation are unclear. Here, we investigate the role of dendritic cell (DC)-dependent T-cell differentiation in autoimmune and antifungal inflammation and find that mammalian sterile 20-like kinase 1 (MST1) signalling from DCs negatively regulates IL-17 producing-CD4+T helper cell (Th17) differentiation. MST1 deficiency in DCs increases IL-17 production by CD4+T cells, whereas ectopic MST1 expression in DCs inhibits it. Notably, MST1-mediated DC-dependent Th17 differentiation regulates experimental autoimmune encephalomyelitis and antifungal immunity. Mechanistically, MST1-deficient DCs promote IL-6 secretion and regulate the activation of IL-6 receptor α/β and STAT3 in CD4+T cells in the course of inducing Th17 differentiation. Activation of the p38 MAPK signal is responsible for IL-6 production in MST1-deficient DCs. Thus, our results define the DC MST1–p38MAPK signalling pathway in directing Th17 differentiation.
Highlights
The differentiation of CD4 þ T cells is widely studied, the mechanisms of antigenpresenting cell-dependent T-cell modulation are unclear
A significant reduction of mammalian sterile 20-like kinase 1 (MST1) mRNA and protein was observed in dendritic cell (DC), but not in macrophages or neutrophils (Supplementary Fig. 1B,C), indicating that Mst1DDC could be used for studies of DC function
To examine whether IL-6R signliang is necessary for the T-cell differentiation induced by DC MST1, we applied an siRNA approach to knockdown of IL-6Ra and IL-6Rb expression in OT-II T cells (Supplementary Fig. 16A,C), which were subsequently co-cultured with wild type (WT) or Mst1DDC DCs in the DC-T-cell co-culture system as described above
Summary
The differentiation of CD4 þ T cells is widely studied, the mechanisms of antigenpresenting cell-dependent T-cell modulation are unclear. MST1 deficiency in DCs does not alter T-cell proliferation (Fig. 2e and Supplementary Fig. 8), but significantly enhances the IL-17 þ cell percentage, IL-17 mRNA expression and IL-17 secretion compared with WT mice, whereas the IFNg þ cell percentage and expression are similar in the two group mice immunized with MOG (Fig. 2e–h).
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