Li Lushen, Shirkey Marina W, Zhang Tianshu, Xiong Yanbao, Piao Wenji, Saxena Vikas, Paluskievicz Christina, Lee Young, Toney Nicholas, Cerel Benjamin M, Li Qinshan, Simon Thomas, Smith Kyle D, Hippen Keli L, Blazar Bruce R, Abdi Reza, Bromberg Jonathan S
Department of Surgery, and.
Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland, USA.
J Clin Invest. 2020 May 1;130(5):2602-2619. doi: 10.1172/JCI135099.
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.
淋巴结基质细胞（LNSCs）通过构建淋巴细胞微环境来调节免疫。LNSC产生的层粘连蛋白α5（Lama5）调节CD4 + T细胞，但其功能的潜在机制尚不清楚。在这里，我们表明，LNSCs中Lama5的缺失导致淋巴结皮质脊（CR）和高内皮静脉（HEV）周围的Lama5蛋白减少。Lama5的缺失影响淋巴结结构，HEV增加，趋化因子和细胞粘附分子上调，并导致T细胞区中调节性T细胞数量增加。Lama5通过α6整合素和α- dystroglycan受体抑制小鼠和人类T细胞跨内皮迁移以及T细胞进入淋巴结。在免疫反应和同种异体移植过程中，Lama5的缺失促进抗原特异性CD4 + T细胞通过HEV进入CR，抑制T细胞活化，并将T细胞分化改变为抑制性调节表型。Lama5的缺失或T细胞Lama5受体的阻断导致同种异体移植接受增强。同种异体移植物中Lama5和Lama4 / Lama5的比例与排斥反应的严重程度相关。总体而言，我们的结果表明，基质Lama5通过改变淋巴结结构和T细胞行为来调节免疫反应。这项研究描绘了一个基质Lama5 - T细胞受体轴，可作为免疫耐受调节的靶点。
