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

Poli, Alessandro and Abdul-Hamid, Shidqiyyah and Zaurito, Antonio Enrico and Campagnoli, Francesca and Bevilacqua, Valeria and Sheth, Bhavwanti and Fiume, Roberta and Pagani, Massimiliano and Abrignani, Sergio and Divecha, Nullin (2021) PIP4Ks impact on PI3K, FOXP3, and UHRF1 signaling and modulate human regulatory T cell proliferation and immunosuppressive activity. Proceedings of the National Academy of Sciences of the United States of America, 118 (31). pp. 1-11. ISSN 0027-8424 E-ISSN 1091-6490

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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.

Item Type: Article (Journal)
Uncontrolled Keywords: Phosphatidylinositol 5-phosphate 4-kinase; T-regulatory cells; UHRF1; immunosuppression; phosphoinositide kinases.
Subjects: Q Science > Q Science (General)
Q Science > QP Physiology
Kulliyyahs/Centres/Divisions/Institutes (Can select more than one option. Press CONTROL button): Kulliyyah of Nursing > Department of Basic Medical Sciences for Nursing
Depositing User: Shidqiyyah Abdul Hamid
Date Deposited: 24 Sep 2021 15:44
Last Modified: 24 Sep 2021 15:44
URI: http://irep.iium.edu.my/id/eprint/92431

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