Regulation of T cell alloimmunity by PI3Kγ and PI3Kδ

Phosphatidylinositol-3-kinases (PI3K) γ and δ are preferentially enriched in leukocytes, and defects in these signaling pathways have been shown to impair T cell activation. The effects of PI3Kγ and PI3Kδ on alloimmunity remain underexplored. Here, we show that both PI3Kγ (−/−) and PI3Kδ (D910A/D910...

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Autores principales: Uehara, Mayuko, McGrath, Martina M., Ohori, Shunsuke, Solhjou, Zhabiz, Banouni, Naima, Routray, Sujit, Evans, Catherine, DiNitto, Jonathan P., Elkhal, Abdallah, Turka, Laurence A., Strom, Terry B., Tullius, Stefan G., Winkler, David G., Azzi, Jamil, Abdi, Reza
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5643371/
https://www.ncbi.nlm.nih.gov/pubmed/29038423
http://dx.doi.org/10.1038/s41467-017-00982-x
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author Uehara, Mayuko
McGrath, Martina M.
Ohori, Shunsuke
Solhjou, Zhabiz
Banouni, Naima
Routray, Sujit
Evans, Catherine
DiNitto, Jonathan P.
Elkhal, Abdallah
Turka, Laurence A.
Strom, Terry B.
Tullius, Stefan G.
Winkler, David G.
Azzi, Jamil
Abdi, Reza
author_facet Uehara, Mayuko
McGrath, Martina M.
Ohori, Shunsuke
Solhjou, Zhabiz
Banouni, Naima
Routray, Sujit
Evans, Catherine
DiNitto, Jonathan P.
Elkhal, Abdallah
Turka, Laurence A.
Strom, Terry B.
Tullius, Stefan G.
Winkler, David G.
Azzi, Jamil
Abdi, Reza
author_sort Uehara, Mayuko
collection PubMed
description Phosphatidylinositol-3-kinases (PI3K) γ and δ are preferentially enriched in leukocytes, and defects in these signaling pathways have been shown to impair T cell activation. The effects of PI3Kγ and PI3Kδ on alloimmunity remain underexplored. Here, we show that both PI3Kγ (−/−) and PI3Kδ (D910A/D910A) mice receiving heart allografts have suppression of alloreactive T effector cells and delayed acute rejection. However, PI3Kδ mutation also dampens regulatory T cells (Treg). After treatment with low dose CTLA4-Ig, PI3Kγ (−/−), but not PI3Κδ (D910A/D910A), recipients exhibit indefinite prolongation of heart allograft survival. PI3Kδ (D910A/D910A) Tregs have increased apoptosis and impaired survival. Selective inhibition of PI3Kγ and PI3Kδ (using PI3Kδ and dual PI3Kγδ chemical inhibitors) shows that PI3Kγ inhibition compensates for the negative effect of PI3Kδ inhibition on long-term allograft survival. These data serve as a basis for future PI3K-based immune therapies for transplantation.
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spelling pubmed-56433712017-10-18 Regulation of T cell alloimmunity by PI3Kγ and PI3Kδ Uehara, Mayuko McGrath, Martina M. Ohori, Shunsuke Solhjou, Zhabiz Banouni, Naima Routray, Sujit Evans, Catherine DiNitto, Jonathan P. Elkhal, Abdallah Turka, Laurence A. Strom, Terry B. Tullius, Stefan G. Winkler, David G. Azzi, Jamil Abdi, Reza Nat Commun Article Phosphatidylinositol-3-kinases (PI3K) γ and δ are preferentially enriched in leukocytes, and defects in these signaling pathways have been shown to impair T cell activation. The effects of PI3Kγ and PI3Kδ on alloimmunity remain underexplored. Here, we show that both PI3Kγ (−/−) and PI3Kδ (D910A/D910A) mice receiving heart allografts have suppression of alloreactive T effector cells and delayed acute rejection. However, PI3Kδ mutation also dampens regulatory T cells (Treg). After treatment with low dose CTLA4-Ig, PI3Kγ (−/−), but not PI3Κδ (D910A/D910A), recipients exhibit indefinite prolongation of heart allograft survival. PI3Kδ (D910A/D910A) Tregs have increased apoptosis and impaired survival. Selective inhibition of PI3Kγ and PI3Kδ (using PI3Kδ and dual PI3Kγδ chemical inhibitors) shows that PI3Kγ inhibition compensates for the negative effect of PI3Kδ inhibition on long-term allograft survival. These data serve as a basis for future PI3K-based immune therapies for transplantation. Nature Publishing Group UK 2017-10-16 /pmc/articles/PMC5643371/ /pubmed/29038423 http://dx.doi.org/10.1038/s41467-017-00982-x Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Uehara, Mayuko
McGrath, Martina M.
Ohori, Shunsuke
Solhjou, Zhabiz
Banouni, Naima
Routray, Sujit
Evans, Catherine
DiNitto, Jonathan P.
Elkhal, Abdallah
Turka, Laurence A.
Strom, Terry B.
Tullius, Stefan G.
Winkler, David G.
Azzi, Jamil
Abdi, Reza
Regulation of T cell alloimmunity by PI3Kγ and PI3Kδ
title Regulation of T cell alloimmunity by PI3Kγ and PI3Kδ
title_full Regulation of T cell alloimmunity by PI3Kγ and PI3Kδ
title_fullStr Regulation of T cell alloimmunity by PI3Kγ and PI3Kδ
title_full_unstemmed Regulation of T cell alloimmunity by PI3Kγ and PI3Kδ
title_short Regulation of T cell alloimmunity by PI3Kγ and PI3Kδ
title_sort regulation of t cell alloimmunity by pi3kγ and pi3kδ
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5643371/
https://www.ncbi.nlm.nih.gov/pubmed/29038423
http://dx.doi.org/10.1038/s41467-017-00982-x
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