Browsing by Author "Shen, Jian"

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    Novel Myh11 Dual Reporter Mouse Model Provides Definitive Labeling and Identification of Smooth Muscle Cells—Brief Report
    (AHA, 2021-02) Ruan, Jian; Zhang, Lu; Hu, Donghua; Qu, Xianghu; Yang, Fan; Chen, Fuxue; He, Xiangqin; Shen, Jian; Dong, Kunzhe; Sweet, Megan; Sanchez, Christina; Li, Deqiang; Shou, Weinian; Zhou, Jiliang; Cai, Chen-Leng; Pediatrics, School of Medicine
    Objective: Myh11 encodes a myosin heavy chain protein that is specifically expressed in smooth muscle cells (SMCs) and is important for maintaining vascular wall stability. The goal of this study is to generate a Myh11 dual reporter mouse line for definitive visualization of MYH11+ SMCs in vivo. Approach and Results: We generated a Myh11 knock-in mouse model by inserting LoxP-nlacZ-4XpolyA-LoxP-H2B-GFP-polyA-FRT-Neo-FRT reporter cassette into the Myh11 gene locus. The nuclear (n) lacZ-4XpolyA cassette is flanked by 2 LoxP sites followed by H2B-GFP (histone 2B fused green fluorescent protein). Upon Cre-mediated recombination, nlacZ-stop cassette is removed thereby permitting nucleus localized H2B-GFP expression. Expression of the nuclear localized lacZ or H2B-GFP is under control of the endogenous Myh11 promoter. Nuclear lacZ was expressed specifically in SMCs at embryonic and adult stages. Following germline Cre-mediated deletion of nuclear lacZ, H2B-GFP was specifically expressed in the nuclei of SMCs. Comparison of nuclear lacZ expression with Wnt1Cre and Mef2cCre mediated-H2B-GFP expression revealed heterogenous origins of SMCs from neural crest and second heart field in the great arteries and coronary vessels adjacent to aortic root. Conclusions: The Myh11 knock-in dual reporter mouse model offers an exceptional genetic tool to visualize and trace the origins of SMCs in mice.
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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.