Browsing by Author "Cui, Weiguo"

Now showing 1 - 4 of 4
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    CXCR5+PD-1+ follicular helper CD8 T cells control B cell tolerance
    (Springer Nature, 2019-09-27) Chen, Yuhong; Yu, Mei; Zheng, Yongwei; Fu, Guoping; Xin, Gang; Zhu, Wen; Luo, Lan; Burns, Robert; Li, Quan-Zhen; Dent, Alexander L.; Zhu, Nan; Cui, Weiguo; Malherbe, Laurent; Wen, Renren; Wang, Demin; Microbiology and Immunology, School of Medicine
    Many autoimmune diseases are characterized by the production of autoantibodies. The current view is that CD4+ T follicular helper (Tfh) cells are the main subset regulating autoreactive B cells. Here we report a CXCR5+PD1+ Tfh subset of CD8+ T cells whose development and function are negatively modulated by Stat5. These CD8+ Tfh cells regulate the germinal center B cell response and control autoantibody production, as deficiency of Stat5 in CD8 T cells leads to an increase of CD8+ Tfh cells, resulting in the breakdown of B cell tolerance and concomitant autoantibody production. CD8+ Tfh cells share similar gene signatures with CD4+ Tfh, and require CD40L/CD40 and TCR/MHCI interactions to deliver help to B cells. Our study thus highlights the diversity of follicular T cell subsets that contribute to the breakdown of B-cell tolerance.
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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.
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    Tissue-resident CD4+ T helper cells assist the development of protective respiratory B and CD8+ T cell memory responses
    (American Association for the Advancement of Science, 2021) Son, Young Min; Cheon, In Su; Wu, Yue; Li, Chaofan; Wang, Zheng; Gao, Xiaochen; Chen, Yao; Takahashi, Yoshimasa; Fu, Yang-Xin; Dent, Alexander L.; Kaplan, Mark H.; Taylor, Justin J.; Cui, Weiguo; Sun, Jie; Microbiology and Immunology, School of Medicine
    Much remains unknown about the roles of CD4+ T helper cells in shaping localized memory B cell and CD8+ T cell immunity in the mucosal tissues. Here, we report that lung T helper cells provide local assistance for the optimal development of tissue-resident memory B and CD8+ T cells after the resolution of primary influenza virus infection. We have identified a population of T cells in the lung that exhibit characteristics of both follicular T helper and TRM cells, and we have termed these cells as resident helper T (TRH) cells. Optimal TRH cell formation was dependent on transcription factors involved in T follicular helper and resident memory T cell development including BCL6 and Bhlhe40. We show that TRH cells deliver local help to CD8+ T cells through IL-21-dependent mechanisms. Our data have uncovered the presence of a tissue-resident helper T cell population in the lung that plays a critical role in promoting the development of protective B cell and CD8+ T cell responses.
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    Uncoupling of macrophage inflammation from self-renewal modulates host recovery from respiratory viral infection
    (Cell Press, 2021) Zhu, Bibo; Wu, Yue; Huang, Su; Zhang, Ruixuan; Son, Young Min; Li, Chaofan; Cheon, In Su; Gao, Xiaochen; Wang, Min; Chen, Yao; Zhou, Xian; Nguyen, Quynh; Phan, Anthony T.; Behl, Supriya; Taketo, M. Mark; Mack, Matthias; Shapiro, Virginia S.; Zeng, Hu; Ebihara, Hideki; Mullon, John J.; Edell, Eric S.; Reisenauer, Janani S.; Demirel, Nadir; Kern, Ryan M.; Chakraborty, Rana; Cui, Weiguo; Kaplan, Mark H.; Zhou, Xiaobo; Goldrath, Ananda W.; Sun, Jie; Microbiology and Immunology, School of Medicine
    Tissue macrophages self-renew during homeostasis and produce inflammatory mediators upon microbial infection. We examined the relationship between proliferative and inflammatory properties of tissue macrophages by defining the impact of the Wnt/β-catenin pathway, a central regulator of self-renewal, in alveolar macrophages (AMs). Activation of β-catenin by Wnt ligand inhibited AM proliferation and stemness, but promoted inflammatory activity. In a murine influenza viral pneumonia model, β-catenin-mediated AM inflammatory activity promoted acute host morbidity; in contrast, AM proliferation enabled repopulation of reparative AMs and tissue recovery following viral clearance. Mechanistically, Wnt treatment promoted β-catenin-HIF-1α interaction and glycolysis-dependent inflammation while suppressing mitochondrial metabolism and thereby, AM proliferation. Differential HIF-1α activities distinguished proliferative and inflammatory AMs in vivo. This β-catenin-HIF-1α axis was conserved in human AMs and enhanced HIF-1α expression associated with macrophage inflammation in COVID-19 patients. Thus, inflammatory and reparative activities of lung macrophages are regulated by β-catenin-HIF-1α signaling, with implications for the treatment of severe respiratory diseases.