Regulation of T cell alloimmunity by PI3K? and PI3K?.

ABSTRACT: Phosphatidylinositol-3-kinases (PI3K) ? and ? are preferentially enriched in leukocytes, and defects in these signaling pathways have been shown to impair T cell activation. The effects of PI3K? and PI3K? on alloimmunity remain underexplored. Here, we show that both PI3K? -/- and PI3K? D910A/D910A mice receiving heart allografts have suppression of alloreactive T effector cells and delayed acute rejection. However, PI3K? mutation also dampens regulatory T cells (Treg). After treatment with low dose CTLA4-Ig, PI3K? -/- , but not PI3?? D910A/D910A , recipients exhibit indefinite prolongation of heart allograft survival. PI3K? D910A/D910A Tregs have increased apoptosis and impaired survival. Selective inhibition of PI3K? and PI3K? (using PI3K? and dual PI3K?? chemical inhibitors) shows that PI3K? inhibition compensates for the negative effect of PI3K? inhibition on long-term allograft survival. These data serve as a basis for future PI3K-based immune therapies for transplantation.Phosphatidylinositol-3-kinases (PI3K) ? and ? are key regulators of T cell signaling. Here the author show, using mouse heart allograft transplantation models, that PI3K? or PI3K? deficiency prolongs graft survival, but selective inhibition of PI3K? or PI3K? reveals alternative transplant survival outcomes post CTLA4-Ig treatment.

SUBMITTER: Uehara M 

PROVIDER: S-EPMC5643371 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature