Browsing by Subject "IRF2"

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    The transcription factor IRF2 drives interferon-mediated CD8+ T cell exhaustion to restrict anti-tumor immunity
    (Elsevier, 2022-12-13) Lukhele, Sabelo; Rabbo, Diala Abd; Guo, Mengdi; Shen, Jian; Elsaesser, Heidi J.; Quevedo, Rene; Carew, Madeleine; Gadalla, Ramy; Snell, Laura M.; Mahesh, Lawanya; Ciudad, M. Teresa; Snow, Bryan E.; You-Ten, Annick; Haight, Jillian; Wakeham, Andrew; Ohashi, Pamela S.; Mak, Tak W.; Cui, Weiguo; McGaha, Tracy L.; Brooks, David G.; Microbiology and Immunology, School of Medicine
    Type 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.