However the differentiation of CD4+T cells is widely studied the mechanisms

However the differentiation of CD4+T cells is widely studied the mechanisms of antigen-presenting cell-dependent T-cell modulation are unclear. the p38 MAPK transmission is responsible for IL-6 production in MST1-deficient DCs. Therefore our results define the DC MST1-p38MAPK signalling pathway in directing Th17 differentiation. CD4+T cells are an essential component of the adaptive immune system and regulate immune responses to foreign antigens1 2 3 4 5 6 The activation and differentiation of CD4+T cells are controlled from the three main signalling components of the T-cell receptor (TCR) (signal 1) co-stimulatory molecules (signal 2) and cytokine receptors (signal 3)4 5 6 7 These signals depend within the regulatory part of innate immune cells. In the Omecamtiv mecarbil presence of cytokines produced by innate immune cells naive CD4+T cells differentiate into helper T-cell subsets with unique functions and cytokine profiles. These include interferon-γ (IFNγ)-generating type 1 helper T (Th1) cells which are essential for immunity to intracellular microorganisms IL-4-generating Th2 cells which protect against parasites and extracellular pathogens4 and Th17 cells that create IL-17A IL-17F IL-21 and IL-22 and protect against bacterial and fungal infections at mucosal surfaces8. Dendritic cells (DCs) are professional Omecamtiv mecarbil antigen-presenting cells (APC) that bridge innate and adaptive immunity. In addition to Omecamtiv mecarbil presenting antigens and modulating cell surface co-stimulatory molecules DC-derived cytokines and chemokines can be proinflammatory or anti-inflammatory and can engage distinct T-cell differentiation programs9. For example the binding of the proinflammatory cytokine IL-6 to a complex of the IL-6 receptor α (IL-6Rα also known as CD126) and IL-6Rβ (Compact disc130; sign transducing receptor gp130) activates the transcription activator STAT3 leading to differentiation of naive CD4+T cells into Th17 cells by inducing the lineage-specific transcription factor RORγt10 11 12 13 14 15 Studies from our lab and others Omecamtiv mecarbil have shown that innate signalling in DCs mediated by G protein-coupled receptor S1P1 (refs 16 17 sirtuin 1 (ref. 18) mitogen-activated protein kinase (MAPKs)19 20 and Wnt-β-catenin21 has a critical role in shaping adaptive immune responses by directing naive CD4+T-cell differentiation. How the differentiation of CD4+T cells is modulated and regulated by innate immune signals in DCs remains to be understood. Mammalian sterile 20-like kinase 1 (MST1) Col4a3 is mammalian class II germinal center protein kinase also known as serine/threonine kinase 4 and kinase responsive to stress 2 (refs 22 23 MST1 has been implicated in regulating the cell cycle and apoptosis in various species24 25 26 27 28 29 MST1 is also involved in regulating adaptive immune cell function30 31 MST1-deficient mice accumulate mature lymphocytes in the thymus and have low numbers of naive T cells in the peripheral lymphoid organs due to a dysregulation of chemotaxis and apoptosis32 33 34 MST1 controls the development and function of regulatory T (Treg) cells through modulation of Foxo1/Foxo3 stability in autoimmune disease35. In addition MST1 regulates the activation of T cells by phosphorylating the cell cycle inhibitory proteins MOBKL1A and MOBKL1B36. Furthermore MST1 is important for optimal reactive oxygen species (ROS) production and bactericidal activity of phagocytes because it promotes the activation of the small GTPase Rac as well as mitochondrial trafficking and juxtaposition to the phagosome through the assembly of a TRAF6-ECSIT complex37. However whether MST1 is involved in bridging the innate immune signal to the adaptive immune response is not clear. Here we show that MST1 has a critical role in directing the T-cell lineage fate by producing DC-derived cytokines which link innate and adaptive immune modulation. Through a p38MAPK-MK2/MSK1-CREB dependent signalling pathway MST1 is required for IL-6 production by DCs as well as for the expression of IL-6Rα/β and phosphorylation of STAT3 in responding T cells resulting in specific lineage engagement of Th17 cells in experimental autoimmune encephalomyelitis (EAE) and fungal infection-induced inflammation. Results Deficiency of MST1 in DCs does not alter DC homoeostasis To Omecamtiv mecarbil investigate the role of MST1 in the immune system we purified many types of mouse immune cells including macrophages (CD11b+F4/80+ cells) DCs (CD11c+MHCII+F4/80?Ly6G?NK1.1?CD19?TCR? cells) neutrophils (CD11b+ Ly6G+ cells) CD4+T cells (CD4+TCR+ cells) and CD8+T cells (CD8+TCR+ cells) as described previously18 and analysed MST1 expression. This showed that MST1 is highly.