MAP4K2 promotes regulatory T cell differentiation and attenuates T cell immunity 2256886

Abstract

MAP4K family kinases are key kinases for T-cell-mediated immune responses; however, in vivo roles of MAP4K2 in immune regulation remain unclear. We used T-cell-specific MAP4K2 conditional knockout (T-MAP4K2 cKO) mice, single-cell RNA sequencing (scRNA-seq), and mass spectrometry analysis to study the role of MAP4K2 in T cell function and regulation. We found that MAP4K2 protein levels were increased in Treg cells compared to other T helper cells. We found that MAP4K2 interacted with DDX39, induced Foxp3 gene expression, and promoted Treg differentiation. Mechanistically, MAP4K2 directly phosphorylated the DEAD box protein DDX39, leading to DDX39 nuclear translocation and subsequent Foxp3 RNA splicing. MAP4K2-induced Foxp3 mRNA levels were abolished in DDX39 knockout Jurkat T cells. Furthermore, T-MAP4K2 cKO mice displayed the reduction of Treg population and sustained inflammation during remission phase of EAE autoimmune disease model. Remarkably, the anti-PD-1 immunotherapeutic effect on pancreatic cancer was drastically improved in T-MAP4K2 cKO mice, Treg-specific MAP4K2-deficient mice, or MAP4K2-inhibitor-treated mice. Consistently, scRNA-seq analysis of human pancreatic or lung cancer patients showed an increase of MAP4K2 levels in the tumor-infiltrating Treg cells; MAP4K2 mRNA levels were correlated with Foxp3 mRNA levels in the tumor-infiltrating T cells. Collectively, MAP4K2 promotes Treg differentiation by inducing DDX39 nuclear translocation, leading to the attenuation of tumor immunity. n/a Immune Response Regulation: Molecular Mechanisms (IRM)