PIP4Ks impact on PI3K, FOXP3, and UHRF1 signaling and modulate human regulatory T cell proliferation and immunosuppressive activity.
Regulatory T cells (Tregs) play fundamental roles in maintaining peripheral tolerance to prevent autoimmunity and limit legitimate immune responses, a feature hijacked in tumor microenvironments in which the recruitment of Tregs often extinguishes immune surveillance through suppression of T-effector cell signaling and tumor cell killing. The pharmacological tuning of Treg activity without impacting on T conventional (Tconv) cell activity would likely be beneficial in the treatment of various human pathologies. PIP4K2A, 2B, and 2C constitute a family of lipid kinases that phosphorylate PtdIns5P to PtdIns(4,5)P 2 They are involved in stress signaling, act as synthetic lethal targets in p53-null tumors, and in mice, the loss of PIP4K2C leads to late onset hyperinflammation. Accordingly, a human single nucleotide polymorphism (SNP) near the PIP4K2C gene is linked with susceptibility to autoimmune diseases. How PIP4Ks impact on human T cell signaling is not known. Using ex vivo human primary T cells, we found that PIP4K activity is required for Treg cell signaling and immunosuppressive activity. Genetic and pharmacological inhibition of PIP4K in Tregs reduces signaling through the PI3K, mTORC1/S6, and MAPK pathways, impairs cell proliferation, and increases activation-induced cell death while sparing Tconv. PIP4K and PI3K signaling regulate the expression of the Treg master transcriptional activator FOXP3 and the epigenetic signaling protein Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1). Our studies suggest that the pharmacological inhibition of PIP4K can reprogram human Treg identity while leaving Tconv cell signaling and T-helper differentiation to largely intact potentially enhancing overall immunological activity.
['Poli|Alessandro|A|0000-0001-5808-820X', 'Abdul-Hamid|Shidqiyyah|S|0000-0003-1767-838X', 'Zaurito|Antonio Enrico|AE|0000-0002-5657-1983', 'Campagnoli|Francesca|F|', 'Bevilacqua|Valeria|V|', 'Sheth|Bhavwanti|B|', 'Fiume|Roberta|R|0000-0001-7757-4000', 'Pagani|Massimiliano|M|0000-0002-7017-9304', 'Abrignani|Sergio|S|0000-0002-0794-3285', 'Divecha|Nullin|N|0000-0001-9695-6039']
UHRF1 immunosuppression Phosphatidylinositol 5-phosphate 4-kinase T-regulatory cells phosphoinositide kinases