IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v8y2017i1d10.1038_s41467-017-00982-x.html
   My bibliography  Save this article

Regulation of T cell alloimmunity by PI3Kγ and PI3Kδ

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 & St, 2017. "Regulation of T cell alloimmunity by PI3Kγ and PI3Kδ," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00982-x
    DOI: 10.1038/s41467-017-00982-x
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-017-00982-x
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-017-00982-x?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00982-x. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.