ALBERT

Description: Retinoic-acid-receptor-related orphan nuclear receptor t (RORt) 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)–RORt 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) phosphorylated AhR at Ser 36 and induced AhR nuclear translocation. AhR also interacted with RORt and transported RORt into the nucleus. IKKβ (inhibitor of nuclear factor B kinase β)–mediated RORt Ser 489 phosphorylation induced the AhR-RORt interaction. T cell receptor (TCR) signaling also induced the novel RORt phosphorylation and subsequent AhR-RORt interaction. Collectively, TCR signaling or GLK overexpression induces IL-17A transcription through the IKKβ-mediated RORt phosphorylation and the AhR-RORt interaction in T cells. Our findings suggest that inhibitors of GLK or the AhR-RORt complex could be used as IL-17A–blocking agents for IL-17A–mediated autoimmune diseases.