ZFP335-MYBL2 transcriptional axis orchestrates Th17 cell differentiation and psoriatic inflammation.

Abstract

T helper 17 (Th17) cell differentiation is governed by a complex transcriptional network centered on the lineage-specifying factor RORγt, accompanied by STAT3, IRF4, and SMAD2/3. However, the complete repertoire of transcriptional regulators controlling Il17a gene transcription and Th17 commitment remains incompletely defined. Here, we identify zinc finger protein 335 (ZFP335) as a critical regulator of Th17 differentiation. Mechanistically, ZFP335 directly binds and activates the Mybl2 promoter, and the resulting MYBL2 protein cooperates with RORγt to drive Il17a transcription. Genetic ablation of Zfp335 attenuated imiquimod-induced psoriasis-like skin inflammation and diminished Th17 cell responses in vivo. Notably, Mybl2 deficiency phenocopied these protective effects. Collectively, these findings establish a ZFP335-MYBL2-IL17A transcriptional axis that governs Th17 differentiation and identify this pathway as a potential therapeutic target for Th17-mediated inflammatory diseases.