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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-effecto...

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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
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spelling my.iium.irep.924312021-09-24T07:44:09Z http://irep.iium.edu.my/92431/ PIP4Ks impact on PI3K, FOXP3, and UHRF1 signaling and modulate human regulatory T cell proliferation and immunosuppressive activity Poli, Alessandro Abdul-Hamid, Shidqiyyah Zaurito, Antonio Enrico Campagnoli, Francesca Bevilacqua, Valeria Sheth, Bhavwanti Fiume, Roberta Pagani, Massimiliano Abrignani, Sergio Divecha, Nullin Q Science (General) QP Physiology 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. National Academy of Sciences 2021-07-26 Article PeerReviewed application/pdf en http://irep.iium.edu.my/92431/1/92431_PIP4Ks%20impact%20on%20PI3K%2C%20FOXP3%2C%20and%20UHRF1%20signaling.pdf application/pdf en http://irep.iium.edu.my/92431/2/92431_PIP4Ks%20impact%20on%20PI3K%2C%20FOXP3%2C%20and%20UHRF1%20signaling_SCOPUS.pdf 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 https://www.pnas.org/content/118/31/e2010053118.short https://doi.org/10.1073/pnas.2010053118
institution Universiti Islam Antarabangsa Malaysia
building IIUM Library
collection Institutional Repository
continent Asia
country Malaysia
content_provider International Islamic University Malaysia
content_source IIUM Repository (IREP)
url_provider http://irep.iium.edu.my/
language English
English
topic Q Science (General)
QP Physiology
spellingShingle Q Science (General)
QP Physiology
Poli, Alessandro
Abdul-Hamid, Shidqiyyah
Zaurito, Antonio Enrico
Campagnoli, Francesca
Bevilacqua, Valeria
Sheth, Bhavwanti
Fiume, Roberta
Pagani, Massimiliano
Abrignani, Sergio
Divecha, Nullin
PIP4Ks impact on PI3K, FOXP3, and UHRF1 signaling and modulate human regulatory T cell proliferation and immunosuppressive activity
description 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.
format Article
author Poli, Alessandro
Abdul-Hamid, Shidqiyyah
Zaurito, Antonio Enrico
Campagnoli, Francesca
Bevilacqua, Valeria
Sheth, Bhavwanti
Fiume, Roberta
Pagani, Massimiliano
Abrignani, Sergio
Divecha, Nullin
author_facet Poli, Alessandro
Abdul-Hamid, Shidqiyyah
Zaurito, Antonio Enrico
Campagnoli, Francesca
Bevilacqua, Valeria
Sheth, Bhavwanti
Fiume, Roberta
Pagani, Massimiliano
Abrignani, Sergio
Divecha, Nullin
author_sort Poli, Alessandro
title PIP4Ks impact on PI3K, FOXP3, and UHRF1 signaling and modulate human regulatory T cell proliferation and immunosuppressive activity
title_short PIP4Ks impact on PI3K, FOXP3, and UHRF1 signaling and modulate human regulatory T cell proliferation and immunosuppressive activity
title_full PIP4Ks impact on PI3K, FOXP3, and UHRF1 signaling and modulate human regulatory T cell proliferation and immunosuppressive activity
title_fullStr PIP4Ks impact on PI3K, FOXP3, and UHRF1 signaling and modulate human regulatory T cell proliferation and immunosuppressive activity
title_full_unstemmed PIP4Ks impact on PI3K, FOXP3, and UHRF1 signaling and modulate human regulatory T cell proliferation and immunosuppressive activity
title_sort pip4ks impact on pi3k, foxp3, and uhrf1 signaling and modulate human regulatory t cell proliferation and immunosuppressive activity
publisher National Academy of Sciences
publishDate 2021
url 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
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score 13.211869

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