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    Home > Active Ingredient News > Immunology News > Nature Sub-Journal/Science/Hepatology Academician Tian Zhigang and other teams have made continuous progress in the field of immunology

    Nature Sub-Journal/Science/Hepatology Academician Tian Zhigang and other teams have made continuous progress in the field of immunology

    • Last Update: 2021-10-01
    • Source: Internet
    • Author: User
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    Editor’s note iNature is China’s largest academic official account.
    It is jointly created by the doctoral team of Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
    The iNature Talent Official Account is now launched, focusing on talent recruitment, academic progress, scientific research information, interested parties can Long press or scan the QR code below to follow us
    .

    iNature natural killer (NK) cells play a key role in anti-tumor immunity, but how their function is regulated by post-transcriptional modifications (for example, N6-methyladenosine (m6A) methylation) is unclear
    .

    On September 17, 2021, Tian Zhigang and Peng Hui from the University of Science and Technology of China published a research paper titled "METTL3-mediated m6A RNA methylation promotes the anti-tumour immunity of natural killer cells" in Nature Communications.
    The research report The expression of m6A "writer" METL3 in tumor-infiltrating NK cells is reduced, and there is a positive correlation between the protein expression level of METL3 and the effector molecules in NK cells
    .

     The study found that the lack of Mettl3 in NK cells can change the homeostasis of NK cells and inhibit the infiltration and function of NK cells in the tumor microenvironment, leading to accelerated tumor development and shortening the survival period of mice
    .

    The gene encoding SHP-2 has been modified by m6A, and its protein expression is reduced in NK cells deficient in METL3
    .

    Decreased SHP-2 activity makes NK cells slow to respond to IL-15, which is related to the inhibitory activation of AKT and MAPK signaling pathways in METL3-deficient NK cells
    .

    These findings indicate that m6A methylation protects the homeostasis of NK cells and tumor immune surveillance functions
    .

    In addition, on September 12, 2021, Peng Hui, Tian Zhigang and Sun Yan from the University of Science and Technology of China published a report entitled "Requirement of RORα for Maintenance and Anti-Tumor Immunity of Liver-Resident Natural Killer Cells/ILC1s" in Hepatology Online.
    Research paper, the study found that RORα is highly expressed in liver-resident NK (LrNK) cells/ILC1s
    .

    LrNK cells/ILC1s in mice subjected to conditional ablation of Rora in LrNK cells/ILC1s and conventional NK (cNK) cells decreased, but the number of cNK cells was normal
    .

    RORα-deficient LrNK cells/ILC1s showed increased apoptosis and significantly altered transcription profiles
    .

    Using a mouse model of colorectal cancer liver metastasis, the study found that RORα conditional defects lead to more radical liver tumor progression and impaired expression of effector molecules in LrNK cells/ILC1
    .

    Therefore, treatment with RORα agonists effectively limits liver metastasis and promotes the expression of effector molecules of LrNK cells/ILC1s
    .

    In summary, this study reveals the previously undefined role of RORα in the maintenance and function of LrNK cells/ILC1, and provides insights for the use of LrNK cell/ILC1 activity in the treatment of liver cancer
    .

    On July 6, 2021, Wei Haiming, Tian Zhigang and Sun Zimin of the University of Science and Technology of China jointly published a research paper entitled "Inflammatory monocytes promote pre-engraftment syndrome and tocilizumab can therapeutically limit pathology in patients" in Nature Communications.
    The research shows GM-CSF produced by cord blood-derived inflammatory monocytes drives PES pathology, and monocytes are the main source of IL-6 during PES
    .

    In addition, the study reports the results of a single-arm, single-center clinical study of tocilizumab in patients with steroid-refractory severe PES
    .

    The study was in line with the main outcome indicator because there were no non-recurrent deaths during the 100-day follow-up period
    .

    The study also met the key secondary outcome indicators for neutrophil engraftment and hematopoiesis
    .

    These findings provide a treatment strategy to address PES and improve non-relapse mortality (click to read)
    .

    On March 21, 2021, Tian Zhigang, Peng Hui, Sun Yan from the University of Science and Technology of China and Eric Vivier from the University of Marseille in France published a study titled "Liver type 1 innate lymphoid cells develop locally via an interferon-γ-dependent loop" in Science.
    The paper, this study found the differentiation potential and regulation mechanism of adult hematopoietic precursor cells into type 1 natural lymphocytes (liver ILC1, that is, liver colonizing NK cells), revealing the new path of natural lymphocytes outside the bone marrow development (click to read)
    .

    As a core component of the innate immune system, natural killer (NK) cells are very important in tumor monitoring
    .

    Unlike adaptive lymphocytes, the activation of NK cells is determined by the integration of signals from the germline-encoded activation and inhibitory receptors
    .

    After activation, NK cells can kill target malignant cells by releasing lysis particles containing perforin and granzyme, and secrete cytokines with potent anti-tumor activity
    .

    At the same time, NK cells can also mediate cytotoxicity through death ligands, such as Fas ligand (FasL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which induce target cell apoptosis
    .

    The effector functions of NK cells are also regulated by soluble molecules
    .

    Among them, interleukin (IL)-15 is a key cytokine that controls the survival, proliferation and activation of NK cells through the IL15 receptor (IL-15R) complex.
    The IL15 receptor (IL-15R) complex is composed of It is composed of α, β chain (CD122) and common γ chain (γc, CD132)
    .

    IL-15Rα is widely expressed on many cell types, and binds to IL-15 with high affinity to form a heterodimer, which presents IL-15 in trans to cells expressing IL-15Rβ-γc
    .

    IL-15Rβ-γc participates in inducing the activation of JAK1/3-STAT5, Ras-MAPK-ERK and PI3K-AKT-mTOR pathways, which has a variety of effects on the biology of NK cells
    .

    However, the regulation of IL-15R downstream signaling pathways is not fully understood
    .

    In recent years, N6-methyladenosine (m6A) modification has attracted much attention due to its universality and importance in eukaryotes
    .

    There are 3 independent components related to m6A modification: "writers", "erasers" and "readers"
    .

    Methyltransferase-like (METTL) 3, METL14, and Wilms’ tumor 1 associated protein (WTAP) belong to “writers” and form the m6A methyltransferase complex, which installs m6A on the target messenger (m)RNA
    .

    Although both METL3 and METL14 contain a methyltransferase domain; studies have shown that METL3 is a catalytically active subunit, and METL14 functions as an RNA binding platform
    .

    m6A modification regulates splicing, translation and stability of mRNA, thereby affecting cell differentiation, proliferation and apoptosis
    .

    For example, the specification and differentiation of hematopoietic stem cells requires m6A modification
    .

    For adaptive immunity, it has been shown that m6A methylation supports the proliferation and differentiation of CD4+ T cells and controls the immunosuppressive function of T regulatory cells
    .

    M6A methylation also inhibits the cross-presentation ability of dendritic cells through family protein 1 (YTHDC1) (a m6A reading protein) containing the YTH domain, thereby inhibiting the anti-tumor response mediated by CD8+ T cells
    .

    Paradoxically, METTL3-mediated m6A methylation promotes the activation of dendritic cells and the ability to initiate T cells
    .

    Although the role of m6A methylation in the immune system is getting more and more attention, its effect on NK cells has only recently begun to be recognized
    .

    A previous study reported that m6A "reader" YTHDF2 can promote NK cell effector function
    .

    However, the function of m6A "writers" and upstream environmental factors in regulating m6A methylation in NK cells is currently unclear
    .

    In this study, it was found that METL3 expression was positively correlated with m6A levels and effector functions of NK cells
    .

    Mice that are conditionally defective in METL3 in NK cells will aggravate tumor progression, and at the same time, the number of NK cells will decrease and the effector function will be impaired
    .

    Further analysis showed that m6A methylation mediated by METTL3 protected the signaling pathway downstream of IL-15R, thereby regulating the response of NK cells to IL-15 in the tumor microenvironment (TME)
    .

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