CDK8/CDK19 inhibition restores T-cell homeostasis in primary immune thrombocytopenia

ABSTRACT: CD4+CD25+Foxp3+ regulatory T cells (Tregs) are pivotal negative regulators of the adaptive immune system. Abnormalities in the number and/or function of Tregs contribute to the pathogenesis of primary immune thrombocytopenia (ITP). Strategies aimed at modulating Tregs offer potential therapeutic opportunities for ITP management. In this study, we demonstrated that inhibition of cyclin-dependent kinase 8 (CDK8) and CDK19 activity by the small-molecule inhibitor AS2863619 (AS) robustly promoted the conversion of CD4+CD25- effector T cells (Teffs) into CD4+CD25+Foxp3+ Tregs, endowing the converted Tregs with lineage stability and potent suppressive capacity. Mechanistically, AS rapidly augmented STAT5 phosphorylation and subsequent Foxp3 induction. STAT5 blockade completely abrogated this effect, confirming that the Treg-promoting activity of AS was critically dependent on STAT5 signaling. In parallel, AS suppressed STAT3 phosphorylation under interleukin-6-driven conditions, thereby attenuating T helper 17 (Th17) polarization. These mechanistic findings were supported by global transcriptomic analysis, which revealed a profound transcriptional shift by broadly suppressing gene programs of Teff differentiation and function while simultaneously upregulating a robust signature characteristic of stable Tregs. Crucially, unbiased upstream analysis of these changes pinpointed STAT5, STAT3, and FOXP3 as the core transcription factors mediating the drug's effect. Functional metabolic analysis further revealed that AS mediated metabolic reprogramming in T cells by suppressing glycolysis, thereby providing the necessary metabolic adaptations for Treg conversion. In a murine model of active ITP, CDK8/CDK19 inhibition elevated Treg frequencies and ameliorated thrombocytopenia in a STAT5-dependent manner. Collectively, our study highlighted the therapeutic potential of CDK8/CDK19 inhibition in restoring immune homeostasis and managing ITP.