Browsing by Author "Guo, Mengdi"

Now showing 1 - 4 of 4
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    Dynamic CD4+ T cell heterogeneity defines subset-specific suppression and PD-L1-blockade-driven functional restoration in chronic infection
    (Springer Nature, 2021) Snell, Laura M.; Xu, Wenxi; Abd-Rabbo, Diala; Boukhaled, Giselle; Guo, Mengdi; Macleod, Bethany L.; Elsaesser, Heidi J.; Hezaveh, Kebria; Alsahafi, Nirmin; Lukhele, Sabelo; Nejat, Sara; Prabhakaran, Ramanandan; Epelman, Slava; McGaha, Tracy L.; Brooks, David G.; Microbiology and Immunology, School of Medicine
    Inhibiting PD-1:PD-L1 signaling has transformed therapeutic immune restoration. CD4+ T cells sustain immunity in chronic infections and cancer, yet little is known about how PD-1 signaling modulates CD4+ helper T (TH) cell responses or the ability to restore CD4+ TH-mediated immunity by checkpoint blockade. We demonstrate that PD-1:PD-L1 specifically suppressed CD4+ TH1 cell amplification, prevents CD4+ TH1 cytokine production and abolishes CD4+ cytotoxic killing capacity during chronic infection in mice. Inhibiting PD-L1 rapidly restored these functions, while simultaneously amplifying and activating TH1-like T regulatory cells, demonstrating a system-wide CD4-TH1 recalibration. This effect coincided with decreased T cell antigen receptor signaling, and re-directed type I interferon (IFN) signaling networks towards dominant IFN-γ-mediated responses. Mechanistically, PD-L1 blockade specifically targeted defined populations with pre-established, but actively suppressed proliferative potential, with limited impact on minimally cycling TCF-1+ follicular helper T cells, despite high PD-1 expression. Thus, CD4+ T cells require unique differentiation and functional states to be targets of PD-L1-directed suppression and therapeutic restoration.
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    Early innate and adaptive immune perturbations determine long-term severity of chronic virus and Mycobacterium tuberculosis coinfection
    (Elsevier, 2021) Xu, Wenxi; Snell, Laura M.; Guo, Mengdi; Boukhaled, Giselle; Macleod, Bethany L.; Li, Ming; Tullius, Michael V.; Guidos, Cynthia J.; Tsao, Ming-Sound; Divangahi, Maziar; Horwitz, Marcus A.; Liu, Jun; Brooks, David G.; Microbiology and Immunology, School of Medicine
    Chronic viral infections increase severity of Mycobacterium tuberculosis (Mtb) coinfection. Here, we examined how chronic viral infections alter the pulmonary microenvironment to foster coinfection and worsen disease severity. We developed a coordinated system of chronic virus and Mtb infection that induced central clinical manifestations of coinfection, including increased Mtb burden, extra-pulmonary dissemination, and heightened mortality. These disease states were not due to chronic virus-induced immunosuppression or exhaustion; rather, increased amounts of the cytokine TNFα initially arrested pulmonary Mtb growth, impeding dendritic cell mediated antigen transportation to the lymph node and subverting immune-surveillance, allowing bacterial sanctuary. The cryptic Mtb replication delayed CD4 T cell priming, redirecting T helper (Th) 1 toward Th17 differentiation and increasing pulmonary neutrophilia, which diminished long-term survival. Temporally restoring CD4 T cell induction overcame these diverse disease sequelae to enhance Mtb control. Thus, Mtb co-opts TNFα from the chronic inflammatory environment to subvert immune-surveillance, avert early immune function, and foster long-term coinfection.
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    Molecular, metabolic, and functional CD4 T cell paralysis in the lymph node impedes tumor control
    (Elsevier, 2023) Guo, Mengdi; Abd-Rabbo, Diala; Bertol, Bruna C.; Carew, Madeleine; Lukhele, Sabelo; Snell, Laura M.; Xu, Wenxi; Boukhaled, Giselle M.; Elsaesser, Heidi; Halaby, Marie Jo; Hirano, Naoto; McGaha, Tracy L.; Brooks, David G.; Microbiology and Immunology, School of Medicine
    CD4 T cells are central effectors of anti-cancer immunity and immunotherapy, yet the regulation of CD4 tumor-specific T (TTS) cells is unclear. We demonstrate that CD4 TTS cells are quickly primed and begin to divide following tumor initiation. However, unlike CD8 TTS cells or exhaustion programming, CD4 TTS cell proliferation is rapidly frozen in place by a functional interplay of regulatory T cells and CTLA4. Together these mechanisms paralyze CD4 TTS cell differentiation, redirecting metabolic circuits, and reducing their accumulation in the tumor. The paralyzed state is actively maintained throughout cancer progression and CD4 TTS cells rapidly resume proliferation and functional differentiation when the suppressive constraints are alleviated. Overcoming their paralysis established long-term tumor control, demonstrating the importance of rapidly crippling CD4 TTS cells for tumor progression and their potential restoration as therapeutic targets.
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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.