HIPK2 directs cell type-specific regulation of STAT3 transcriptional activity in Th17 cell differentiation

T helper 17 (Th17) cells are important in adaptive immunity and are also implicated in inflammatory and autoimmune disorders. Th17 cell differentiation from naïve CD4+ T cells is tightly regulated in gene transcription through coordinated activities of the signal-responsive transcription factor STAT3 (signal transducer and activator of transcription 3), the pioneering factors IRF4/BATF, and the Th17-specific transcription factor RORγT, which support Th17 immune functions. Given that STAT3 acts as a master transcription factor in different cell types, whether STAT3 is regulated in a Th17-specific manner has remained a major unanswered question. In this study, we report that in mouse Th17 cells, Stat3 phosphorylation at serine 727, required for its transcriptional activity, is carried out by homeodomain-interacting protein kinase 2 (Hipk2), a nuclear kinase selectively up-regulated in Th17 cells, but not other Th subtypes that have distinct functions in immunity. Unexpectedly, we found that Hipk2 transcriptional expression is directed by Stat3 itself in Th17 cells and that, upon expression, Hipk2 in turn phosphorylates Stat3 at S727 that potentiates Stat3 activity for transcriptional activation of Th17 signature genes such as Il17a/f to ensure productive Th17 cell differentiation. We validated the in vivo function of Hipk2 for Th17 cell development in T cell-induced colitis in mice using Hipk2-knockout mice. Our study presents a previously unrecognized mechanism of self-directed cell type-specific regulation of the master transcription factor Stat3 through its own transcriptional target Hipk2 in Th17 cell differentiation, and suggests a therapeutic strategy for developing a targeted therapy for Th17-associated inflammatory disorders.