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.

doi:10.1101/2025.01.29.635520

bioRxiv · 10.1101/2025.01.29.635520

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.

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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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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.. 2025-02-02. Lytic IFNγ is stored in granzyme B-containing cytotoxic granules and co-secreted by effector CD8⁺ T cells. https://doi.org/10.1101/2025.01.29.635520

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