An Emerging Role for Serine Protease Inhibitors in T Lymphocyte Immunity and Beyond

Figure 4

Spi6 protects CTL from self-inflicted damage. Spi6 inhibits GrB-mediated apoptosis of CTLs. Spi6 inhibits GrB in the cytoplasm of wild-type (WT) CTLs (nucleus in dark gray), through the formation of an irreversible complex. The inhibition of GrB (crossed line) blocks the cleavage and activation of target enzymes and the induction of death (crossed line). The breakdown of granules integrity and the release of more GrB, either directly by cytoplasmic GrB or downstream targets, is thus inhibited by Spi6. Cytoplasmic GrB is not blocked in Spi6 KO CTLs and so there is increased death. A positive feedback loop whereby GrB releases into the cytoplasm catalyzes further leakage from granules then ensues because GrB causes granule damage. There is no GrB-mediated breakdown of granules in GrB KO CTLs resulting in increased granule number and decreased death.