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Regulation of T cell alloimmunity by PI3Kγ and PI3Kδ.

Authors: 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|||Reza Abdi

Journal: Nature communications

Publication Type: Journal Article

Date: 2017

DOI: PMC5643371

ID: 29038423

Affiliations:

Affiliations

    Transplantation Research Center, Renal Division, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue, Boston, MA, 02115, USA.|||Transplantation Research Center, Renal Division, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue, Boston, MA, 02115, USA.|||Transplantation Research Center, Renal Division, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue, Boston, MA, 02115, USA.|||Transplantation Research Center, Renal Division, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue, Boston, MA, 02115, USA.|||Transplantation Research Center, Renal Division, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue, Boston, MA, 02115, USA.|||Transplantation Research Center, Renal Division, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue, Boston, MA, 02115, USA.|||Infinity Pharmaceuticals, Inc 784 Memorial Drive, Cambridge, MA, 02139, USA.|||Infinity Pharmaceuticals, Inc 784 Memorial Drive, Cambridge, MA, 02139, USA.|||Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA.|||Center for Transplantation Sciences, Massachusetts General Hospital/Harvard Medical School, Massachusetts Massachusetts General Hospital-East Charlestown Navy Yard Building 149, 13th Street, Charlestown, MA, 02129-2020, USA.|||The Transplant Institute, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Avenue, E/CLS Room 607, Boston, MA, 02215, USA.|||Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA.|||Infinity Pharmaceuticals, Inc 784 Memorial Drive, Cambridge, MA, 02139, USA.|||Transplantation Research Center, Renal Division, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue, Boston, MA, 02115, USA.|||Transplantation Research Center, Renal Division, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue, Boston, MA, 02115, USA. rabdi@rics.bwh.harvard.edu.

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 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 , recipients exhibit indefinite prolongation of heart allograft survival. PI3Kδ 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.Phosphatidylinositol-3-kinases (PI3K) γ and δ are key regulators of T cell signaling. Here the author show, using mouse heart allograft transplantation models, that PI3Kγ or PI3Kδ deficiency prolongs graft survival, but selective inhibition of PI3Kγ or PI3Kδ reveals alternative transplant survival outcomes post CTLA4-Ig treatment.


Chemical List

    Immunosuppressive Agents|||Abatacept|||Class I Phosphatidylinositol 3-Kinases|||Class Ib Phosphatidylinositol 3-Kinase|||Pik3cd protein, mouse|||Pik3cg protein, mouse

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