Regulation of T cell alloimmunity by PI3Kγ and PI3Kδ

Mayuko Uehara, Martina M. McGrath, Shunsuke Ohori, Zhabiz Solhjou, Naima Banouni, Sujit Routray, Catherine Evans, Jonathan P. DiNitto, Abdallah Elkhal, Laurence A. Turka, Terry B. Strom, Stefan G. Tullius, David G. Winkler, Jamil Azzi and Reza Abdi ()
Additional contact information
Mayuko Uehara: Brigham and Women’s Hospital and Harvard Medical School
Martina M. McGrath: Brigham and Women’s Hospital and Harvard Medical School
Shunsuke Ohori: Brigham and Women’s Hospital and Harvard Medical School
Zhabiz Solhjou: Brigham and Women’s Hospital and Harvard Medical School
Naima Banouni: Brigham and Women’s Hospital and Harvard Medical School
Sujit Routray: Brigham and Women’s Hospital and Harvard Medical School
Catherine Evans: Infinity Pharmaceuticals
Jonathan P. DiNitto: Infinity Pharmaceuticals
Abdallah Elkhal: Brigham and Women’s Hospital and Harvard Medical School
Laurence A. Turka: Massachusetts General Hospital/Harvard Medical School
Terry B. Strom: Beth Israel Deaconess Medical Center/Harvard Medical School
Stefan G. Tullius: Brigham and Women’s Hospital and Harvard Medical School
David G. Winkler: Infinity Pharmaceuticals
Jamil Azzi: Brigham and Women’s Hospital and Harvard Medical School
Reza Abdi: Brigham and Women’s Hospital and Harvard Medical School

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-00982-x

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