Although PI3K is usually associated with cell survival, T cells from both patients with APDS and Pik3cdE1020K/+ mice exhibit heightened TCR-induced apoptosis (Angulo et al., 2013; Bier et al., 2019), resulting in part from early and increased expression of Fasl, a known target of IL-2-STAT5 (Ross and Cantrell, 2018), AKT, and HIF-1α-pathways (Finlay et al., 2012; Macintyre et al., 2011). Here, HIF1A is linked to activated PI3K-delta syndrome.