Category: Organ transplantation
Background.Accumulation of TEMRA CD8 (CD45RA+CCR7-CD28-CD27-) in kidney transplant recipients (KTR) with a stable graft function is associated with an increased risk of kidney graft dysfunction. Upon TCR and IL-15 stimulation, TEMRA CD8 activates the endothelium by secreting high amount of IFNg and TNFa.
Aim.Migration of T cells to inflamed tissue is crucial for their immune effector function, especially in the context of transplantation. In this study, we aim to characterize the migratory properties of TEMRA CD8 from KTR by analysing their adhesion and their transmigration across endothelial cell barrier and we investigate the ability of metabolic interferences to prevent the migration of TEMRA CD8 to inflamed site.
Results.With a high expression of VLA-4, LFA-1 and glycosylated PSGL1, we show that TEMRA CD8 from KTR in resting state can adhere and transmigrate across endothelial cell barrier following the CXCL12 gradient. Short term IL-15 stimulation fosters the expression of glycosylated PSGL1 and consequently increases the binding to P-Selectin, the adhesion and the transmigration capacity of TEMRA CD8. Finally, we show that glycolysis and mitochondrial respiration were instrumental for the migration of TEMRA CD8 whereas the inhibition of these 2 processes has only a modest impact on EM trafficking.
Conclusion. Our data demonstrate that TEMRA CD8 from KTR have a high potential to migrate to inflammatory site in response to gradient of CXCL12. Their migration could be blunt by targeting the interaction between glycosylated PSGL1 and P-selectin that can be disrupted either directly at PSGL1 or indirectly via metabolic pathways.
Tra My Doan Ngoc– PhD student, CRTI UMR1064, INSERM, Université de Nantes
Gaelle Tilly– Engineer, CRTI UMR1064, INSERM, Université de Nantes
Sarah Bruneau– Post-doc, CRTI UMR1064, INSERM, Université de Nantes
Alexandre Glemain– PhD student, CRTI UMR1064, INSERM, Université de Nantes
Pierrick Guerif– Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes
Magali Giral– PU-PH, CRTI UMR1064, INSERM, Université de Nantes
Sophie Brouard– Centre de Recherche en Transplantation et Immunologie (CRTI) UMR 1064, INSERM, Université de Nantes, ITUN, CHU de Nantes
Claire Pecqueur– Research Scientist, Centre de Recherche en Cancérologie et Immunologie Nantes-Angers, UMR1232 INSERM, Université de Nantes
Nicolas Degauque– Research Scientist, CRTI UMR1064, INSERM, Université de Nantes