000170085 001__ 170085
000170085 005__ 20260318155254.0
000170085 0247_ $$2doi$$a10.1038/s41423-026-01391-1
000170085 0248_ $$2sideral$$a148648
000170085 037__ $$aART-2026-148648
000170085 041__ $$aeng
000170085 100__ $$aLi, Xuemei
000170085 245__ $$aLytic IFNγ is stored in cytotoxic granules and coreleased with granzyme B to mediate cytotoxic T lymphocyte killing
000170085 260__ $$c2026
000170085 5060_ $$aAccess copy available to the general public$$fUnrestricted
000170085 5203_ $$aCytotoxic T lymphocytes (CTLs) eliminate target cells by forming immunological synapses and releasing effector molecules, including interferon gamma (IFNγ). However, how IFNγ contributes to cytotoxicity remains unclear. Here, we identify a subset of IFNγ stored within granzyme B⁺ cytotoxic granules (CGs) in activated mouse and human CTLs, which we term lytic IFNγ. This CG-associated IFNγ represents the primary pool released in a polarized manner at the immunological synapse together with canonical lytic molecules. Lytic IFNγ is present in tumor-infiltrating CTLs and is cosecreted with granzyme B (GzmB) in both soluble form and as part of supramolecular attack particles (SMAPs). Functional assays indicate that IFNγ contributes to CTL-mediated tumor cell death by acting in concert with granzyme B and perforin to increase cytotoxicity and promote apoptosis via the IFNγ–STAT1–caspase-3 pathway. CTLs lacking the vesicle priming factor Munc13-4 exhibit impaired release of both CGs and early-phase IFNγ. However, prolonged synapse engagement restores IFNγ secretion at distal membrane sites, revealing a second, nonpolarized IFNγ pool. Consistently, endogenous IFNγ is detected in both CG-enriched and multivesicular body (MVB)-enriched fractions. We propose that while lytic IFNγ is released from CGs at the synapse to directly promote target cell killing, nonpolarized IFNγ secretion originates from MVBs or small vesicles during sustained activation. Together, these findings reveal a previously unrecognized mechanism of IFNγ storage and release, establishing lytic IFNγ as a critical effector component of CTL cytotoxicity and antitumor immunity.
000170085 536__ $$9info:eu-repo/grantAgreement/ES/AEI/PID2024-157582OB-I00$$9info:eu-repo/grantAgreement/ES/DGA/B29-23R$$9info:eu-repo/grantAgreement/ES/DGA/LMP139-21
000170085 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttps://creativecommons.org/licenses/by/4.0/deed.es
000170085 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000170085 700__ $$aSchirra, Claudia
000170085 700__ $$aWirkner, Marie-Louise
000170085 700__ $$aTu, Szu-Min
000170085 700__ $$aLin, Chin-Hsin
000170085 700__ $$aHohmann, Meltem
000170085 700__ $$aGu, Yuan
000170085 700__ $$0(orcid)0000-0002-1861-5981$$aSantiago, Llipsy
000170085 700__ $$0(orcid)0000-0003-0154-0730$$aPardo, Julian$$uUniversidad de Zaragoza
000170085 700__ $$aArretxe, Iñaki
000170085 700__ $$aAlawar, Nadia
000170085 700__ $$aChouaib, Abed Alrahman
000170085 700__ $$aBecherer, Ute
000170085 700__ $$aLee, Po-Hsien
000170085 700__ $$aHsu, Hao-Jen
000170085 700__ $$aLaschke, Matthias W.
000170085 700__ $$aBaldari, Cosima T.
000170085 700__ $$aDustin, Michael L.
000170085 700__ $$aRettig, Jens
000170085 700__ $$aKrause, Elmar
000170085 700__ $$aChang, Hsin-Fang
000170085 7102_ $$11011$$2566$$aUniversidad de Zaragoza$$bDpto. Microb.Ped.Radio.Sal.Pú.$$cÁrea Inmunología
000170085 773__ $$g(2026), [17 pp.]$$pCell. mol. immunol.$$tCellular & Molecular Immunology$$x1672-7681
000170085 8564_ $$s6575290$$uhttps://zaguan.unizar.es/record/170085/files/texto_completo.pdf$$yVersión publicada
000170085 8564_ $$s2772904$$uhttps://zaguan.unizar.es/record/170085/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000170085 909CO $$ooai:zaguan.unizar.es:170085$$particulos$$pdriver
000170085 951__ $$a2026-03-18-13:51:54
000170085 980__ $$aARTICLE