Lytic IFNγ is stored in granzyme B-containing cytotoxic granules and co-secreted by effector CD8⁺ T cells
Li, X.; Schirra, C.; Tu, S.-M.; Wirkner, M.-L.; Lin, C.-H.; Hohmann, M.; Alawar, N.; Chouaib, A.; Becherer, U.; Pattu, V.; Rettig, J.; Krause, E.; Chang, H.-F.
Show abstract
Cytotoxic CD8 T cells form immunological synapses with target cells and release effector molecules, including IFN{gamma}, to mediate antitumor immunity. However, the mechanisms by which IFN{gamma} contributes to cytotoxicity remain incompletely understood. Here, we identify a subset of IFN{gamma} stored within GzmB cytotoxic granules (CGs) in activated mouse and human CD8 T cells, termed lytic IFN{gamma}. Lytic IFN{gamma} is polarized to the synapse and co-secreted with GzmB in both soluble and supramolecular attack particle (SMAP)-associated forms. Mouse CD8 T cells lacking the vesicle priming factor Munc13-4 exhibit impaired both CG and early IFN{gamma} release at the immunological synapse, while prolonged synaptic engagement restores IFN{gamma} secretion. Super-resolution imaging demonstrates that sustained synaptic interactions drive IFN{gamma} secretion at distal membrane sites, suggesting the existence of distinct IFN{gamma} populations with potentially diverse functions beyond lytic IFN{gamma}. These findings uncover an unrecognized mechanism of IFN{gamma} storage and release, underscoring its pivotal role in CD8 T cell-mediated tumor elimination.
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