Lukhele, SabeloRabbo, Diala AbdGuo, MengdiShen, JianElsaesser, Heidi J.Quevedo, ReneCarew, MadeleineGadalla, RamySnell, Laura M.Mahesh, LawanyaCiudad, M. TeresaSnow, Bryan E.You-Ten, AnnickHaight, JillianWakeham, AndrewOhashi, Pamela S.Mak, Tak W.Cui, WeiguoMcGaha, Tracy L.Brooks, David G.2024-04-242024-04-242022-12-13Lukhele, S., Rabbo, D. A., Guo, M., Shen, J., Elsaesser, H. J., Quevedo, R., Carew, M., Gadalla, R., Snell, L. M., Mahesh, L., Ciudad, M. T., Snow, B. E., You-Ten, A., Haight, J., Wakeham, A., Ohashi, P. S., Mak, T. W., Cui, W., McGaha, T. L., & Brooks, D. G. (2022). The transcription factor IRF2 drives interferon-mediated CD8+ T cell exhaustion to restrict anti-tumor immunity. Immunity, 55(12), 2369-2385.e10. https://doi.org/10.1016/j.immuni.2022.10.020https://hdl.handle.net/1805/40194Type I and II interferons (IFNs) stimulate pro-inflammatory programs that are critical for immune activation, but also induce immune-suppressive feedback circuits that impede control of cancer growth. Here, we sought to determine how these opposing programs are differentially induced. We demonstrated that the transcription factor interferon regulatory factor 2 (IRF2) was expressed by many immune cells in the tumor in response to sustained IFN signaling. CD8+ T cell-specific deletion of IRF2 prevented acquisition of the T cell exhaustion program within the tumor and instead enabled sustained effector functions that promoted long-term tumor control and increased responsiveness to immune checkpoint and adoptive cell therapies. The long-term tumor control by IRF2-deficient CD8+ T cells required continuous integration of both IFN-I and IFN-II signals. Thus, IRF2 is a foundational feedback molecule that redirects IFN signals to suppress T cell responses and represents a potential target to enhance cancer control.en-USPublisher Policyinterferon regulatory factor 2IRF2type I interferoninterferon gammaCD8+ T cellsT cell exhaustionimmunotherapyadoptive cell transferCyTOFArticle