Institut National de la Santé et de la Recherche Médicale, Nantes Université, CHU Nantes, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France.
CHU Nantes, Nantes Université, Institut de Transplantation Urologie Néphrologie, Nantes, France.
J Am Soc Nephrol. 2022 Dec;33(12):2211-2231. doi: 10.1681/ASN.2022030286. Epub 2022 Oct 24.
The mechanisms regulating CD8 T cell migration to nonlymphoid tissue during inflammation have not been fully elucidated, and the migratory properties of effector memory CD8 T cells that re-express CD45RA (TEMRA CD8 T cells) remain unclear, despite their roles in autoimmune diseases and allotransplant rejection.
We used single-cell proteomic profiling and functional testing of CD8 T cell subsets to characterize their effector functions and migratory properties in healthy volunteers and kidney transplant recipients with stable or humoral rejection.
We showed that humoral rejection of a kidney allograft is associated with an accumulation of cytolytic TEMRA CD8 T cells in blood and kidney graft biopsies. TEMRA CD8 T cells from kidney transplant recipients exhibited enhanced migratory properties compared with effector memory (EM) CD8 T cells, with enhanced adhesion to activated endothelium and transmigration in response to the chemokine CXCL12. CXCL12 directly triggers a purinergic P2×4 receptor-dependent proinflammatory response of TEMRA CD8 T cells from transplant recipients. The stimulation with IL-15 promotes the CXCL12-induced migration of TEMRA and EM CD8 T cells and promotes the generation of functional PSGL1, which interacts with the cell adhesion molecule P-selectin and adhesion of these cells to activated endothelium. Although disruption of the interaction between functional PSGL1 and P-selectin prevents the adhesion and transmigration of both TEMRA and EM CD8 T cells, targeting VLA-4 or LFA-1 (integrins involved in T cell migration) specifically inhibited the migration of TEMRA CD8 T cells from kidney transplant recipients.
Our findings highlight the active role of TEMRA CD8 T cells in humoral transplant rejection and suggest that kidney transplant recipients may benefit from therapeutics targeting these cells.
在炎症过程中，调节 CD8 T 细胞向非淋巴组织迁移的机制尚未完全阐明，尽管效应记忆 CD8 T 细胞（重新表达 CD45RA 的 TEMRA CD8 T 细胞）在自身免疫性疾病和同种异体移植排斥中发挥作用，但它们的迁移特性仍不清楚。
我们使用单细胞蛋白质组学分析和 CD8 T 细胞亚群的功能测试，来描述它们在健康志愿者和稳定或体液性排斥的肾移植受者中的效应功能和迁移特性。
我们表明，肾移植的体液性排斥与血液和肾移植物活检中细胞毒性 TEMRA CD8 T 细胞的积累有关。与效应记忆（EM）CD8 T 细胞相比，肾移植受者的 TEMRA CD8 T 细胞表现出增强的迁移特性，对激活的内皮细胞的黏附性增强，并对趋化因子 CXCL12 发生迁移。CXCL12 直接触发移植受者的 TEMRA CD8 T 细胞的嘌呤能 P2X4 受体依赖性促炎反应。IL-15 的刺激促进 TEMRA 和 EM CD8 T 细胞的 CXCL12 诱导迁移，并促进功能 PSGL1 的生成，该分子与细胞黏附分子 P-选择素相互作用，并促进这些细胞与激活的内皮细胞的黏附。虽然功能 PSGL1 与 P-选择素的相互作用的破坏阻止了 TEMRA 和 EM CD8 T 细胞的黏附和迁移，但靶向 VLA-4 或 LFA-1（参与 T 细胞迁移的整合素）特异性抑制了来自肾移植受者的 TEMRA CD8 T 细胞的迁移。
我们的研究结果强调了 TEMRA CD8 T 细胞在体液性移植排斥中的积极作用，并表明肾移植受者可能受益于针对这些细胞的治疗。
