Effector Memory–Expressing CD45RA (TEMRA) CD8+ T Cells from Kidney Transplant Recipients Exhibit Enhanced Purinergic P2X4 Receptor–Dependent Proinflammatory and Migratory Responses
Authors: Doan Ngoc Tra-My , Tilly Gaëlle , Danger Richard , Bonizec Orianne , Masset Christophe , Guérif Pierrick , Bruneau Sarah , Glemain Alexandre , Harb Jean , Cadoux Marion , Vivet Anaïs , Mai Hoa Le , Garcia Alexandra , Laplaud David , Liblau Roland , Giral Magali , Blandin Stéphanie , Feyeux Magalie , Dubreuil Laurence , Pecqueur Claire , Cyr Matthew , Ni Weiming , Brouard Sophie , Degauque Nicolas 
Published: October 2022

Significance StatementThe pathogenic role of terminally differentiated effector memory (TEMRA) CD8+T cells has been implicated in kidney transplant failure. The authors showed that humoral rejection of kidney allografts is associated with an accumulation of cytolytic TEMRA CD8+T cells in blood and in kidney graft biopsies. They demonstrated that TEMRA CD8+T cells from kidney transplant recipients exhibit enhanced migratory properties compared with effector memory CD8+T cells and that the chemokine CXCL12 not only promotes migration of TEMRA CD8+T cells toward nonlymphoid organs but also triggers a purinergic P2X4 receptor–dependent proinflammatory response. They also found that agents aimed at potential TEMRA CD8+T cell–specific targets inhibited the migration of TEMRA CD8+T cells from kidney transplant recipients, suggesting a possible strategy in treating kidney transplant failure.BackgroundThe 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.MethodsWe 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.ResultsWe 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.ConclusionsOur 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.