Chemotaxis overrides the killing response in alloreactive CTLs, providing vascular immune privilege during cellular rejection
Thomas Barba, … , Faddi G. Lakkis, Olivier Thaunat
Thomas Barba, … , Faddi G. Lakkis, Olivier Thaunat
Published May 28, 2025
Citation Information: J Clin Invest. 2025;135(14):e155191. https://doi.org/10.1172/JCI155191.
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Research Article Immunology Nephrology

Chemotaxis overrides the killing response in alloreactive CTLs, providing vascular immune privilege during cellular rejection

Abstract

Graft endothelial cells (ECs) express donor alloantigens and encounter cytotoxic T lymphocytes (CTLs) but are generally spared during T cell–mediated rejection (TCMR), which predominantly affects epithelial structures. The mechanisms underlying this vascular immune privilege are unclear. Transcriptomics analyses and endothelial-mesenchymal transition assessments confirmed that the graft endothelium was preserved during TCMR. Coculture experiments revealed that endothelial and epithelial cells were equally susceptible to CTL-mediated lysis, ruling out cell-intrinsic protection. Intravital microscopy of murine kidney grafts and single-cell RNA-Seq of human renal allografts demonstrated that CTL interactions with ECs were transient compared with epithelial cells. This disparity was mediated by a chemotactic gradient produced by graft stromal cells, guiding CTLs away from ECs toward epithelial targets. In vitro, chemotaxis overrode T cell receptor–induced cytotoxicity, preventing endothelial damage. Finally, analysis of TCMR biopsies revealed that disruption of the chemotactic gradient correlated with endothelialitis lesions, linking its loss to vascular damage. These findings challenge the traditional view of cell-intrinsic immune privilege, proposing a cell-extrinsic mechanism, in which chemotaxis preserves graft vasculature during TCMR. This mechanism may have implications beyond transplantation, highlighting its role in maintaining vascular integrity across pathological conditions.

Authors

Thomas Barba, Martin Oberbarnscheidt, Gregory Franck, Chantal Gao, Sebastien This, Maud Rabeyrin, Candice Roufosse, Linda Moran, Alice Koenig, Virginie Mathias, Carole Saison, Valérie Dubois, Nicolas Pallet, Dany Anglicheau, Baptiste Lamarthée, Alexandre Hertig, Emmanuel Morelon, Arnaud Hot, Helena Paidassi, Thierry Defrance, Antonio Nicoletti, Jean-Paul Duong Van Huyen, Yi-Chung Xu-Dubois, Faddi G. Lakkis, Olivier Thaunat

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Figure 5

Disruption of the chemokine gradient associates with endothelial damage in clinical TCMR.

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Disruption of the chemokine gradient associates with endothelial damage ...
(A–C) ciGENC cells were cultured to confluence under flow conditions, and their morphology was monitored in real time by video microscopy. (A) Representative bright-field images. The first column (No effect) shows ciGENC morphology in the absence of CTLs, while the other columns show their response to the addition of either nonspecific CTLs or allospecific CTLs. Where indicated, CXCL12 was incorporated into the coating beneath the ciGENC. Interactions between CTLs and ciGENC are marked with orange arrowheads. (B) Magnified time-lapse sequence illustrating the morphological changes of a ciGENC engaged by an allospecific CTL (red) in the absence of CXCL12. (C) Quantification of ciGENC morphological changes over time across the different experimental conditions. (D–F) Comparison of the CXCL12 gradient in 12 TCMR kidney graft biopsies with (v >0, purple, n = 6) or without (v = 0, orange, n = 6) endothelialitis (D) Banff i (faded color) and t (dark color) scores for each biopsy are plotted. (E) Representative images of CXCL12 staining (left column) (scale bar: 75 μm) and corresponding computer-assisted quantification of the chemotactic gradient (right column). Percentages of biopsy surface area (F) and staining intensity (G) for CXCL12 were compared between TCMR kidney graft biopsies with (purple, End+) and without (orange, End–) endothelialitis. *P < 0.05, by nonparametric Mann-Whitney U test. Data are presented as median ± IQR (F and G).