@article{33a3a67ba33545f5b53be833e54bca3d,
title = "Cross-Reactive Donor-Specific CD8+ Tregs Efficiently Prevent Transplant Rejection",
abstract = "To reduce the use of non-specific immunosuppressive drugs detrimental to transplant patient health, therapies in development aim to achieve antigen-specific tolerance by promoting antigen-specific regulatory T cells (Tregs). However, identification of the natural antigens recognized by Tregs and the contribution of their dominance in transplantation has been challenging. We identify epitopes derived from distinct major histocompatibility complex (MHC) class II molecules, sharing a 7-amino acid consensus sequence positioned in a central mobile section in complex with MHC class I, recognized by cross-reactive CD8+ Tregs, enriched in the graft. Antigen-specific CD8+ Tregs can be induced in vivo with a 16-amino acid-long peptide to trigger transplant tolerance. Peptides derived from human HLA class II molecules, harboring the rat consensus sequence, also activate and expand human CD8+ Tregs, suggesting its potential in human transplantation. Altogether, this work should facilitate the development of therapies with peptide epitopes for transplantation and improve our understanding of CD8+ Treg recognition.",
keywords = "CD8, antigen-specific, human, peptide, rat, regulation, therapy, tolerance, transplantation",
author = "Elodie Picarda and S{\'e}verine B{\'e}zie and Lorena Usero and Jason Ossart and Marine Besnard and Hanim Halim and Klara Echasserieau and Claire Usal and Jamie Rossjohn and Karine Bernardeau and St{\'e}phanie Gras and Carole Guillonneau",
note = "Funding Information: We thank Dr. Ignacio Anegon for critical reading of the manuscript. We thank Emmanuel Merieau for technical assistance in animal models and Bernard Martinet for purification of OX8 antibodies. We thank the Monash Macromolecular Crystallization Facility staff for assistance with crystallization and the staff at the Australian synchrotron for assistance with data collection. We thank the Vector Core of the University Hospital of Nantes, which is supported by the Association Fran{\c c}aise Contre les Myopathies, for producing the adenoviral vectors. We thank the Fondation Progreffe for financial support and Cr{\'e}dit Agricole for the donation of the FACSAria. This work was realized in the context of the Labex IGO program and IHU-Cesti project supported by the National Research Agency via the investment of the future program (ANR-11-LABX-0016-01 and ANR-10-IBHU-005). The IHU-Cesti project is also supported by Nantes Metropole and the Pays de la Loire Region. This work was supported by an ESOT Junior Basic Science Grant, a Marie Curie fellowship from the 6th FP of the EU, and an Etoiles Montantes from Pays de la Loire to C.G. E.P. was supported by an INSERM-Region Pays de la Loire Fellowship, J.O. was supported by the Fondation pour la Recherche M{\'e}dicale (PLP20141031245), and J.R. is supported by an ARC Laureate Fellowship. S.G. is a Monash Senior Research Fellow. E.P. contributed to data collection, experimentation, analysis, and writing of the manuscript. S.B. L.U. J.O. H.H. M.B. K.E. C.U. and K.B. contributed to data collection, experimentation, and analysis. J.R. and S.G. solved the crystal structure and contributed to data collection and experimentation. C.G. conceived, financed, and led the project, analyzed the data, and wrote the manuscript. Patents have been filed based on the results presented in the paper. Funding Information: We thank Dr. Ignacio Anegon for critical reading of the manuscript. We thank Emmanuel Merieau for technical assistance in animal models and Bernard Martinet for purification of OX8 antibodies. We thank the Monash Macromolecular Crystallization Facility staff for assistance with crystallization and the staff at the Australian synchrotron for assistance with data collection. We thank the Vector Core of the University Hospital of Nantes, which is supported by the Association Fran{\c c}aise Contre les Myopathies , for producing the adenoviral vectors. We thank the Fondation Progreffe for financial support and Cr{\'e}dit Agricole for the donation of the FACSAria. This work was realized in the context of the Labex IGO program and IHU-Cesti project supported by the National Research Agency via the investment of the future program ( ANR-11-LABX-0016-01 and ANR-10-IBHU-005 ). The IHU-Cesti project is also supported by Nantes Metropole and the Pays de la Loire Region . This work was supported by an ESOT Junior Basic Science Grant , a Marie Curie fellowship from the 6th FP of the EU , and an Etoiles Montantes from Pays de la Loire to C.G. E.P. was supported by an INSERM-Region Pays de la Loire Fellowship , J.O. was supported by the Fondation pour la Recherche M{\'e}dicale ( PLP20141031245 ), and J.R. is supported by an ARC Laureate Fellowship . S.G. is a Monash Senior Research Fellow. Publisher Copyright: {\textcopyright} 2019 The Author(s)",
year = "2019",
month = dec,
day = "24",
doi = "10.1016/j.celrep.2019.11.106",
language = "English (US)",
volume = "29",
pages = "4245--4255.e6",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "13",
}
