2025/02/02 by Xuemei Li, Claudia Schirra, Marie-Louise Wirkner +10 · 1 voice
Immunology and Microbiology · #Immune Cell Function and Interaction #Immunotherapy and Immune Responses #T-cell and B-cell Immunology
paper · pdf · doi:10.1101/2025.01.29.635520
openalex publication_date 2025/02/02 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/14
Abstract Cytotoxic CD8⁺ T cells form immunological synapses with target cells and release effector molecules, including IFNγ, to mediate antitumor immunity. However, the mechanisms by which IFNγ contributes to cytotoxicity remain incompletely understood. Here, we identify a subset of IFNγ stored within GzmB⁺ cytotoxic granules (CGs) in activated mouse and human CD8⁺ T cells, termed ’lytic IFNγ’. Lytic IFNγ 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 IFNγ release at the immunological synapse, while prolonged synaptic engagement restores IFNγ secretion. Super-resolution imaging demonstrates that sustained synaptic interactions drive IFNγ secretion at distal membrane sites, suggesting the existence of distinct IFNγ populations with potentially diverse functions beyond lytic IFNγ. These findings uncover an unrecognized mechanism of IFNγ storage and release, underscoring its pivotal role in CD8⁺ T cell-mediated tumor elimination.