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    The lymph node stromal laminin α5 shapes alloimmunity

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    Author
    Li, L.
    Shirkey, M.W.
    Zhang, T.
    Xiong, Y.
    Piao, W.
    Saxena, V.
    Paluskievicz, C.
    Lee, Y.
    Toney, N.
    Cerel, B.M.
    Li, Q.
    Simon, T.
    Bromberg, J.S.
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    Date
    2020
    Journal
    Journal of Clinical Investigation
    Publisher
    American Society for Clinical Investigation
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1172/JCI135099
    Abstract
    Lymph node stromal cells (LNSCs) regulate immunity through constructing lymphocyte niches. LNSC-produced laminin α5 (Lama5) regulates CD4+ T cells but the underlying mechanisms of its functions are poorly understood. Here we show that depleting Lama5 in LNSCs resulted in decreased Lama5 protein in the LN cortical ridge (CR) and around high endothelial venules (HEVs). Lama5 depletion affected LN structure with increased HEVs, upregulated chemokines, and cell adhesion molecules, and led to greater numbers of Tregs in the T cell zone. Mouse and human T cell transendothelial migration and T cell entry into LNs were suppressed by Lama5 through the receptors α6 integrin and α-dystroglycan. During immune responses and allograft transplantation, depleting Lama5 promoted antigen-specific CD4+ T cell entry into the CR through HEVs, suppressed T cell activation, and altered T cell differentiation to suppressive regulatory phenotypes. Enhanced allograft acceptance resulted from depleting Lama5 or blockade of T cell Lama5 receptors. Lama5 and Lama4/Lama5 ratios in allografts were associated with the rejection severity. Overall, our results demonstrated that stromal Lama5 regulated immune responses through altering LN structures and T cell behaviors. This study delineated a stromal Lama5–T cell receptor axis that can be targeted for immune tolerance modulation.
    Sponsors
    This study was supported by NIH grants 1R01AI114496 and R01AI062765, R6029-07, R01 HL11879, P01 AI056299, and NCI P01 CA067493.
    Keyword
    lymph node stromal cells
    Receptors, Laminin
    Immunity
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85084201235&doi=10.1172%2fJCI135099&partnerID=40&md5=bb6c9d6a1afbee0418fe498e54fe6c04; http://hdl.handle.net/10713/12780
    ae974a485f413a2113503eed53cd6c53
    10.1172/JCI135099
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