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

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 P2x4 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.

Automated summary

Our study reveals that humoral rejection of kidney transplants is associated with the accumulation of TEMRA CD8(+) T cells in blood and kidney graft biopsies. TEMRA CD8(+) T cells from kidney transplant recipients show enhanced migratory properties compared to EM CD8(+) T cells, with increased adhesion to activated endothelium and transmigration in response to CXCL12 chemokine. Furthermore, IL-15 stimulation promotes the migration of TEMRA and EM CD8(+) T cells induced by CXCL12 and enhances the generation of functional PSGL1, which interacts with P-selectin and facilitates adhesion to activated endothelium. Notably, inhibiting the migration of TEMRA CD8(+) T cells from kidney transplant recipients by targeting VLA-4 or LFA-1 suggests the potential therapeutic benefit of targeting these cells in transplant recipients.