Abstract 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 T cell trafficking deficiency autoimmune disease models and adoptive immunotherapy models. We identified PDLIM4 and S1P1 as significantly down-regulated target genes in JMJD3-deficient CD4+ T cells by gene profiling and ChIP-seq analyses. The further study showed that PDLIM4 regulate actin cytoskeleton, thus serving as a key regulator of T cell trafficking. These results demonstrate that manipulating JMJD3 expression can benefit autoimmune disease treatment and generate better T cell grafts for adoptive immunotherapy.