The lymph node stromal laminin [alpha]5 shapes alloimmunity

Lymph node stromal cells (LNSCs) regulate immunity through constructing lymphocyte niches. LNSC-produced laminin [alpha]5 (Lama5) regulates [CD4.sup.+] 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 [alpha]6 integrin and [alpha]-dystroglycan. During immune responses and allograft transplantation, depleting Lama5 promoted antigen-specific [CD4.sup.+] 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.
Introduction The lymph node (LN) is the central hub that exchanges antigen-presenting cells and immune cells with peripheral tissues or blood, permitting T cells to encounter cognate antigens and orchestrating [...]