Expressing CD45RA (TEMRA) CD8+ T Cells from Kidney Transplant Recipients Exhibit Enhanced Purinergic P2X4 Receptor-Dependent Proinflammatory and Migratory Responses - INRAE - Institut national de recherche pour l’agriculture, l’alimentation et l’environnement Access content directly
Journal Articles Journal of the American Society of Nephrology Year : 2022

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 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.

Dates and versions

hal-03543095 , version 1 (25-01-2022)

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Tra-My Doan Ngoc, Gaëlle Tilly, Richard Danger, Orianne Bonizec, Christophe Masset, et al.. Expressing CD45RA (TEMRA) CD8+ T Cells from Kidney Transplant Recipients Exhibit Enhanced Purinergic P2X4 Receptor-Dependent Proinflammatory and Migratory Responses. Journal of the American Society of Nephrology, 2022, 33 (12), pp.2211-2231. ⟨10.1681/ASN.2022030286⟩. ⟨hal-03543095⟩
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