TY - JOUR T1 - The self-peptide repertoire plays a critical role in transplant tolerance induction JF - bioRxiv DO - 10.1101/2020.11.09.359968 SP - 2020.11.09.359968 AU - Eric T. Son AU - Pouya Faridi AU - Moumita Paul-Heng AU - Mario Leong AU - Kieran English AU - Sri H. Ramarathinam AU - Asolina Braun AU - Nadine L. Dudek AU - Ian E. Alexander AU - Leszek Lisowski AU - Patrick Bertolino AU - David G. Bowen AU - Anthony W. Purcell AU - Nicole A. Mifsud AU - Alexandra F. Sharland Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/07/20/2020.11.09.359968.abstract N2 - While direct allorecognition underpins both solid organ allograft rejection and tolerance induction, the specific molecular targets of most directly-alloreactive CD8+ T cells have not been defined. In this study, we used a combination of genetically-engineered MHC class I (MHC I) constructs, mice with a hepatocyte-specific mutation in the class I antigen-presentation pathway and immunopeptidomic analysis to provide definitive evidence for the contribution of the peptide cargo of allogeneic MHC I molecules to transplant tolerance induction. We established a systematic approach for the discovery of directly-recognised pMHC epitopes, and identified 17 strongly immunogenic H-2Kb-associated peptides recognised by CD8+ T cells from B10.BR (H-2k) mice, 13 of which were also recognised by BALB/c (H-2d) mice. As few as five different tetramers used together were able to identify a high proportion of alloreactive T cells within a polyclonal population, suggesting that there are immunodominant allogeneic MHC-peptide complexes that can account for a large component of the alloresponse.Competing Interest StatementE.T.S., M.P-H., A.F.S. (University of Sydney) and N.A.M., A.W.P., P.F., N.L.D. (Monash University) are named as co-inventors in a patent application filed by the University of Sydney and Monash University (PCT/AU2020/051221) covering the identification and use of certain peptides described in the publication. ER -