Chemotaxis overrides the killing response in alloreactive CTLs, providing vascular immune privilege during cellular rejection
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
- Emmanuel Morélon (ORCID: https://orcid.org/0000-0001-9928-1671)
- G Franck (ORCID: https://orcid.org/0000-0002-4288-9034)
- Jean–Paul Duong Van Huyen (ORCID: https://orcid.org/0000-0002-3051-2141)
- Sébastien This (ORCID: https://orcid.org/0000-0003-2931-9050)
- Thomas Barba (ORCID: https://orcid.org/0000-0003-1281-0433)
- Martin H. Oberbarnscheidt (ORCID: https://orcid.org/0000-0003-2040-809X)
- Antonino Nicoletti (ORCID: https://orcid.org/0000-0002-2623-0897)
- Valérie Dubois (ORCID: https://orcid.org/0000-0002-1169-7697)
- Linda Moran
- Carole Saison (ORCID: https://orcid.org/0000-0001-5898-7176)
- Thierry Defrance (ORCID: https://orcid.org/0000-0002-6943-358X)
- Alexandre Hertig (ORCID: https://orcid.org/0000-0002-2903-3303)
- Candice Roufosse (ORCID: https://orcid.org/0000-0002-6490-4290)
- Chong Gao (ORCID: https://orcid.org/0000-0001-7639-0808)
- Olivier Thaunat (ORCID: https://orcid.org/0000-0002-3648-8963)
- Maud Rabeyrin (ORCID: https://orcid.org/0000-0003-0713-3271)
- Dany Anglicheau
- Helena Païdassi (ORCID: https://orcid.org/0000-0001-9915-4365)
- Faddi G Lakkis
- Alice Koenig (ORCID: https://orcid.org/0000-0003-4358-9719)
- Nicolas Pallet (ORCID: https://orcid.org/0000-0002-8486-3596)
- Baptiste Lamarthée (ORCID: https://orcid.org/0000-0002-8417-1661)
- A. Hot
- Yi-Chun Xu-Dubois (ORCID: https://orcid.org/0000-0002-8785-5751)
- Virginie Mathias
Institutions
- Université Claude Bernard Lyon 1 (FR)
- École Normale Supérieure de Lyon (FR)
- Hôpital Necker-Enfants Malades (FR)
- Centre National de la Recherche Scientifique (FR)
- Imperial College Healthcare NHS Trust (GB)
- Inserm (FR)
- University of Pittsburgh (US)
- Sorbonne Université (FR)
- Institut Necker Enfants Malades (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Hospices Civils de Lyon (FR)
- North West London Pathology (GB)
- Laboratoire de Biochimie (FR)
- Laboratoire de Recherche Vasculaire Translationnelle (FR)
- Hôpital Tenon (FR)
- Imperial College London (GB)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-05-22
- DOI
- https://doi.org/10.1172/jci155191
- Citations
- 4
- Primary Topic
- Chemokine receptors and signaling
- Type
- article
- Field-Weighted Citation Impact
- 4.18
Funders
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Hospices Civils de Lyon