JMJD3 regulates CD4⁺ T cell trafficking by targeting actin cytoskeleton regulatory gene Pdlim4

Histone H3K27 demethylase JMJD3 plays a critical role in gene expression and T cell differentiation. However, the role and mechanisms of JMJD3 in T cell trafficking remain poorly understood. Here, we show that JMJD3 deficiency in CD4+ T cells resulted in an accumulation of T cells in the thymus and reduction of T cell number in the secondary lymphoid organs. We identified PDLIM4 as a significantly downregulated target gene in JMJD3-deficient CD4+ T cells by gene profiling and ChIP-Seq analyses. We further showed that PDLIM4 functioned as an adaptor protein to interact with sphingosine-1 phosphate receptor 1 (S1P1) and filamentous actin (F-actin), thus serving as a key regulator of T cell trafficking. Mechanistically, JMJD3 bound to the promoter and gene-body regions of the Pdlim4 gene and regulated its expression by interacting with zinc finger transcription factor KLF2. Our findings have identified Pdlim4 as a JMJD3 target gene that affects T cell trafficking by cooperating with S1P1 and have provided insights into the molecular mechanisms by which JMJD3 regulates genes involved in T cell trafficking.