T-cell signaling in Th17-mediated inflammation

[[abstract]]MAP kinase kinase kinase kinases (MAP4Ks) are a subfamily of mammalian Ste20-like serine/threonine kinases that activate the JNK kinase cascade. We have cloned and characterized three MAP4Ks, namely HPK1 (MAP4K1), GLK (MAP4K3) and HGK (MAP4K4). Epigenetic downregulation of HGK (MAP4K4) in T cell results in differentiation of IL-6+ Th17 cells, which play important roles in the pathogenesis of Asia-prevalent non-obese T2D. HPK1 (MAP4K1) is a negative regulator of T-cell signaling through phosphorylation and sequential ubiquitination of the T-cell adaptor SLP-76. GLK (MAP4K3) also interacts with SLP-76 but does not negatively regulate SLP-76. GLK activates PKC-θ during TCR signaling; GLK-deficient mice showed impaired Th17 differentiation. T-cell specific GLK transgenic mice spontaneously developed autoimmune diseases with an induction of systemic inflammation. We found that GLK signaling specifically induced IL-17A transcription in the T cells of GLK transgenic mice. We will present the data on a novel signal transduction mechanism of IL-17A transcriptional activation of AhR and RORγt by GLK in inflammatory T cells and activated T cells. In addition, we found that GLK negatively regulated differentiation and activity of Treg cells through IKKβ. Collectively, MAP4K3/GLK plays a critical role in IL-17A-induced inflammation