Serpins in memory T-cell development. Stimulation of a naïve CD8 T cell with pMHC and costimulation results in proliferation and differentiation into (A) a fully differentiated CTL, which is susceptible to self-administered lethal hits (lightening bolt) by GrB. Inhibition of GrB by Spi6 in mice or PI9 in humans protects CTL from PCD. Naïve CD8 T cells also differentiate into memory-cell precursors that are characterized by lower levels of GrB and Spi6. (B). MTL-precursors escape PCD facilitating the development of MTL independent of GrB and Spi6 (C). Expression of Spi2A in MTL is triggered by the IL-15 survival cytokine and required homeostatic proliferative self-renewal through the suppression of cathepsin-mediated PCD. (D) Upon reexposure to pMHC MTL give rise to expansion into secondary CTL, the survival of which requires protection by Spi6 from GrB-mediated PCD.