The lymph node stromal laminin α5 shapes alloimmunity
Lushen Li, … , Reza Abdi, Jonathan S. Bromberg
Lushen Li, … , Reza Abdi, Jonathan S. Bromberg
Published February 4, 2020
Citation Information: J Clin Invest. 2020;130(5):2602-2619. https://doi.org/10.1172/JCI135099.
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Research Article Immunology

The lymph node stromal laminin α5 shapes alloimmunity

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.

Authors

Lushen Li, Marina W. Shirkey, Tianshu Zhang, Yanbao Xiong, Wenji Piao, Vikas Saxena, Christina Paluskievicz, Young Lee, Nicholas Toney, Benjamin M. Cerel, Qinshan Li, Thomas Simon, Kyle D. Smith, Keli L. Hippen, Bruce R. Blazar, Reza Abdi, Jonathan S. Bromberg

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Figure 4

Lama5 regulates T cell migration via α6 integrin and αDG.

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Lama5 regulates T cell migration via α6 integrin and αDG. (A) CD4+ T cel...
(A) CD4+ T cell track length and velocity migrating on surfaces coated with laminin α4β1γ1 (laminin 411) and/or α5β1γ1 (laminin 511) (2 μg/mL each) measured with real-time live imaging (n = 6). (B) αDG gene transcripts in various T cell subsets relative to hypoxanthine phosphoribosyltransferase (HPRT) measured by qRT-PCR (n = 4). (C) Track length and velocity of CD4+ T cells treated with blocking mAbs against α6 integrin (10 μg/mL, isotype IgG) or αDG (5 μg/mL, isotype IgM) (n = 6). (D) CD4+ T cell binding to 96-well flat-bottom plates coated with laminin 411 and/or 511 (2 μg/mL each), plus anti-CD3 (50 μg/mL) or CCL21 (500 ng/mL) (n = 8). Data (mean ± SEM) are representative of 3 experiments. *P < 0.05; **P < 0.01; ***P < 0.001 by 1-way ANOVA with Tukey’s multiple-comparisons test.