| First Author | Uehara M | Year | 2017 |
| Journal | Nat Commun | Volume | 8 |
| Issue | 1 | Pages | 951 |
| PubMed ID | 29038423 | Mgi Jnum | J:254898 |
| Mgi Id | MGI:6100139 | Doi | 10.1038/s41467-017-00982-x |
| Citation | Uehara M, et al. (2017) Regulation of T cell alloimmunity by PI3Kgamma and PI3Kdelta. Nat Commun 8(1):951 |
| abstractText | Phosphatidylinositol-3-kinases (PI3K) gamma and delta are preferentially enriched in leukocytes, and defects in these signaling pathways have been shown to impair T cell activation. The effects of PI3Kgamma and PI3Kdelta on alloimmunity remain underexplored. Here, we show that both PI3Kgamma (-/-) and PI3Kdelta (D910A/D910A) mice receiving heart allografts have suppression of alloreactive T effector cells and delayed acute rejection. However, PI3Kdelta mutation also dampens regulatory T cells (Treg). After treatment with low dose CTLA4-Ig, PI3Kgamma (-/-) , but not PI3Kappadelta (D910A/D910A) , recipients exhibit indefinite prolongation of heart allograft survival. PI3Kdelta (D910A/D910A) Tregs have increased apoptosis and impaired survival. Selective inhibition of PI3Kgamma and PI3Kdelta (using PI3Kdelta and dual PI3Kgammadelta chemical inhibitors) shows that PI3Kgamma inhibition compensates for the negative effect of PI3Kdelta inhibition on long-term allograft survival. These data serve as a basis for future PI3K-based immune therapies for transplantation.Phosphatidylinositol-3-kinases (PI3K) gamma and delta are key regulators of T cell signaling. Here the author show, using mouse heart allograft transplantation models, that PI3Kgamma or PI3Kdelta deficiency prolongs graft survival, but selective inhibition of PI3Kgamma or PI3Kdelta reveals alternative transplant survival outcomes post CTLA4-Ig treatment. |
