Regulation of T cell alloimmunity by PI3Kγ and PI3Kδ

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 PI3K gamma and PI3K delta on alloimmunity remain underexplored. Here, we show that both PI3K gamma(-/-) and PI3K delta(D910A/D910A) mice receiving heart allografts have suppression of alloreactive T effector cells and delayed acute rejection. However, PI3K delta mutation also dampens regulatory T cells (Treg). After treatment with low dose CTLA4-Ig, PI3K gamma(-/-), but not PI3K delta(D910A/D910A), recipients exhibit indefinite prolongation of heart allograft survival. PI3K delta(D910A/D910A) Tregs have increased apoptosis and impaired survival. Selective inhibition of PI3K gamma and PI3K delta (using PI3K delta and dual PI3K gamma delta chemical inhibitors) shows that PI3K gamma inhibition compensates for the negative effect of PI3K delta inhibition on long-term allograft survival. These data serve as a basis for future PI3K-based immune therapies for transplantation.