Effector Memory-Expressing CD45RA (TEMRA) CD8+ T Cells from Kidney Transplant Recipients Exhibit Enhanced Purinergic P2X4 Receptor-Dependent Proinflammatory and Migratory Responses

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: adhesion molecule; cell activation; cell adhesion; chemokine; chronic allograft rejection; endothelium; immunology; kidney transplantation; lymphocytes; purinergic P2X4 receptors.