Department of Surgery and.
Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland, USA.
J Clin Invest. 2022 Jul 1;132(13). doi: 10.1172/JCI156994.
Lymph node (LN) fibroblastic reticular cells (FRCs) define LN niches and regulate lymphocyte homeostasis through producing diverse extracellular matrix (ECM) components. We examined the role of ECM laminin α4 (Lama4) using FRC-Lama4 conditional KO Pdgfrb-Cre-/- × Lama4fl/fl mice. Single-cell RNA-sequencing (scRNA-Seq) data showed the promoter gene Pdgfrb was exclusively expressed in FRCs. Depleting FRC-Lama4 reduced Tregs and dendritic cells, decreased high endothelial venules, impaired the conduit system, and downregulated T cell survival factors in LNs. FRC-Lama4 depletion impaired the homing of lymphocytes to LNs in homeostasis and after allografting. Alloantigen-specific T cells proliferated, were activated to greater degrees in LNs lacking FRC-Lama4, and were more prone to differentiate into effector phenotypes relative to the Treg phenotype. In murine cardiac transplantation, tolerogenic immunosuppression was not effective in FRC-Lama4 recipients, which produced more alloantibodies than WT. After lung transplantation, FRC-Lama4-KO mice had more severe graft rejection with fewer Tregs in their LNs. Overall, FRC-Lama4 critically contributes to a tolerogenic LN niche by supporting T cell migration, constraining T cell activation and proliferation, and promoting Treg differentiation. Hence, it serves as a therapeutic target for immunoengineering.
淋巴结（LN）纤维母细胞网状细胞（FRC）通过产生多种细胞外基质（ECM）成分来定义 LN 龛位并调节淋巴细胞稳态。我们使用 FRC-Lama4 条件性 KO Pdgfrb-Cre-/- × Lama4fl/fl 小鼠研究了 ECM 层粘连蛋白 α4（Lama4）的作用。单细胞 RNA 测序（scRNA-Seq）数据显示启动子基因 Pdgfrb 仅在 FRC 中表达。FRC-Lama4 的缺失减少了调节性 T 细胞和树突状细胞，降低了高内皮小静脉，损害了导管系统，并下调了 LN 中的 T 细胞存活因子。FRC-Lama4 的缺失损害了淋巴细胞在稳态和同种异体移植后归巢到 LN 的能力。同种抗原特异性 T 细胞增殖，在缺乏 FRC-Lama4 的 LN 中被激活到更高的程度，并且相对于 Treg 表型更容易分化为效应表型。在小鼠心脏移植中，FRC-Lama4 受体中耐受免疫抑制无效，其产生的同种抗体比 WT 多。在肺移植后，FRC-Lama4-KO 小鼠的移植物排斥更严重，其 LN 中的 Treg 更少。总体而言，FRC-Lama4 通过支持 T 细胞迁移、限制 T 细胞激活和增殖以及促进 Treg 分化，对耐受 LN 龛位至关重要。因此，它可作为免疫工程的治疗靶点。
