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

被引：20

作者：

Ngoc, Tra-My Doan ^{[1
]}

Tilly, Gaelle ^{[1
]}

Danger, Richard ^{[1
,2
]}

Bonizec, Orianne ^{[1
]}

Masset, Christophe ^{[1
,2
]}

Guerif, Pierrick ^{[1
,2
]}

Bruneau, Sarah ^{[1
]}

Glemain, Alexandre ^{[1
]}

Harb, Jean ^{[1
,2
]}

Cadoux, Marion ^{[1
]}

Vivet, Anais ^{[1
]}

Le Mai, Hoa ^{[1
,2
]}

Garcia, Alexandra ^{[1
]}

Laplaud, David ^{[1
]}

Liblau, Roland ^{[3
,4
]}

Giral, Magali ^{[1
,2
]}

Blandin, Stephanie ^{[5
]}

Feyeux, Magalie ^{[5
]}

Dubreuil, Laurence ^{[6
]}

Pecqueur, Claire ^{[7
]}

Cyr, Matthew ^{[8
]}

Ni, Weiming ^{[8
]}

Brouard, Sophie ^{[1
,2
]}

Degauque, Nicolas ^{[1
]}

机构：

[1] Nantes Univ, Ctr Res Transplantat & Translat Immunol, Inst Natl Sante & Rech Med, UMR 1064,CHU Nantes, Nantes, France

[2] Nantes Univ, Inst Transplantat Urol Nephrol, CHU Nantes, Nantes, France

[3] Univ Toulouse, Toulouse Inst Infect & Inflammatory Dis Infin, Inst Natl Sante & Rech Med, CNRS,UPS, Toulouse, France

[4] Toulouse Univ Hosp, Dept Immunol, Toulouse, France

[5] Univ Nantes, Inst Natl Sante & Rech Med, BioCore, SFR Bonamy,CHU Nantes,US16,CNRS, Nantes, France

[6] Oniris, INRAE, APEX PAnTher, Nantes, France

[7] Nantes Univ, Univ Angers, Inst Natl Sante & Rech Med, CNRS,CRCI2NA, Nantes, France

[8] IsoPlexis Corp, Branford, CT USA

来源：

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY | 2022年 / 33卷 / 12期

关键词：

cell adhesion; chemokine; lymphocytes; kidney transplantation; immunology; endothelium; chronic allograft rejection; cell activation; adhesion molecule; MAINTENANCE THERAPY; CHEMOKINE RECEPTORS; EXTRACELLULAR ATP; IN-VITRO; IL-15; GENE; ACTIVATION; EXPRESSION; TRANSCRIPTS; VEDOLIZUMAB;

D O I：

10.1681/ASN.2022030286

中图分类号：

R5 [内科学]; R69 [泌尿科学（泌尿生殖系疾病）];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：2211 / 2231

页数：21