Journal
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
Volume 33, Issue 12, Pages 2211-2231Publisher
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2022030286
Keywords
cell adhesion; chemokine; lymphocytes; kidney transplantation; immunology; endothelium; chronic allograft rejection; cell activation; adhesion molecule
Categories
Funding
- LabEX IGO program - Agence Nationale de la Recherche (ANR) via the Investment into the Future program [ANR-11-LABX-0016-01]
- Fondation Centaure
- French government via the Investment into the Future program [ANR-10-IBHU-005]
- Agence Nationale de la Recherche grant [ANR-10-INBS-04]
- ANR project BIKET [ANR-17-CE17-0008]
- ANR project KTD-innov [ANR-17-RHUS-0010]
- Nantes Metropole
- Pays de la Loire Region
- Fondation pour l'Aide a la Recherche sur la Sclerose en Plaques
- Fondation de Cooperation Scientifique Campus Paris-Saclay
- European Union [602470]
- Agence Nationale de la Recherche (ANR) [ANR-17-RHUS-0010] Funding Source: Agence Nationale de la Recherche (ANR)
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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.
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.
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