GLK-IKKβ signaling induces dimerization and translocation of the AhR-RORγt complex in IL-17A induction and autoimmune disease

Retinoic-acid-receptor-related orphan nuclear receptor gamma t (ROR gamma t) controls the transcription of interleukin-17A (IL-17A), which plays critical roles in the pathogenesis of autoimmune diseases. Severity of several human autoimmune diseases is correlated with frequencies of germinal center kinase-like kinase (GLK) (also known as MAP4K3)-overexpressing T cells; however, the mechanism of GLK overexpression-induced autoimmunity remains unclear. We report the signal transduction converging on aryl hydrocarbon receptor (AhR)-ROR gamma t interaction to activate transcription of the IL-17A gene in T cells. T cell-specific GLK transgenic mice spontaneously developed autoimmune diseases with selective induction of IL-17A in T cells. In GLK transgenic T cells, protein kinase C. (PKC theta) phosphorylated AhR at Ser(36) and induced AhR nuclear translocation. AhR also interacted with ROR gamma t and transported ROR gamma t into the nucleus. IKK beta (inhibitor of nuclear factor kappa B kinase beta)-mediated ROR gamma t Ser489 phosphorylation induced the AhR-ROR gamma t interaction. T cell receptor (TCR) signaling also induced the novel ROR gamma t phosphorylation and subsequent AhR-ROR gamma t interaction. Collectively, TCR signaling or GLK overexpression induces IL-17A transcription through the IKK beta-mediated ROR gamma t phosphorylation and the AhR-ROR gamma t interaction in T cells. Our findings suggest that inhibitors of GLK or the AhR-ROR gamma t complex could be used as IL-17A-blocking agents for IL-17A-mediated autoimmune diseases.