PIP4Ks impact on PI3K, FOXP3, and UHRF1 signaling and modulate human regulatory T cell proliferation and immunosuppressive activity

• Main Authors: Poli, Alessandro, Abdul-Hamid, Shidqiyyah, Zaurito, Antonio Enrico, Campagnoli, Francesca, Bevilacqua, Valeria, Sheth, Bhavwanti, Fiume, Roberta, Pagani, Massimiliano, Abrignani, Sergio, Divecha, Nullin
• Format: Article
• Language: English; English
• Published: National Academy of Sciences 2021
• Subjects: Q Science (General); QP Physiology
• Online Access: http://irep.iium.edu.my/92431/1/92431_PIP4Ks%20impact%20on%20PI3K%2C%20FOXP3%2C%20and%20UHRF1%20signaling.pdf; http://irep.iium.edu.my/92431/2/92431_PIP4Ks%20impact%20on%20PI3K%2C%20FOXP3%2C%20and%20UHRF1%20signaling_SCOPUS.pdf; http://irep.iium.edu.my/92431/; https://www.pnas.org/content/118/31/e2010053118.short; https://doi.org/10.1073/pnas.2010053118
• Institution: Universiti Islam Antarabangsa Malaysia

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.