The self-peptide repertoire plays a critical role in transplant tolerance induction.

Eric T Son,Mario L Leong,Leszek Lisowski,Nicole A Mifsud,Patrick Bertolino,Moumita Paul-Heng,Pouya Faridi,Sri H Ramarathinam,Ian E Alexander,Nadine L Dudek,Alexandra F Sharland,Asolina Braun,David G Bowen,Kieran English,Anthony W Purcell

doi:10.1172/jci146771

Abstract

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 major histocompatibility complex 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 recognized pMHC epitopes and identified 17 strongly immunogenic H-2Kb-associated peptides recognized by CD8+ T cells from B10.BR (H-2k) mice, 13 of which were also recognized by BALB/c (H-2d) mice. As few as 5 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.

Highlights

Allorecognition may result in either graft rejection, graft versus host disease, or transplantation tolerance, depending on the context in which the recipient immune system encounters the allogeneic major histocompatibility complex (MHC)
single chain trimer (SCT) molecules were expressed on transduced hepatocytes at equivalent levels to the heterotrimer formed by transgenic H-2Kb heavy chain (HC) with native β2m and peptide (Figure 1B)
Direct allorecognition refers to the engagement of recipient TCRs by intact allogeneic MHC molecules on the surface of donor cells

Summary

Introduction

Allorecognition may result in either graft rejection, graft versus host disease, or transplantation tolerance, depending on the context in which the recipient immune system encounters the allogeneic major histocompatibility complex (MHC). When donor MHC class I (MHC I) molecules are expressed in the hepatocytes of recipient mice, subsequent skin or pancreatic islet grafts bearing the same donor allomorph are accepted indefinitely [1,2,3]. Insights from this model can inform our understanding of allorecognition and transplant tolerance induction more broadly. Many alloreactive T cell clones recognize epitopes comprising allogeneic MHC I molecules complexed with self-peptides [5,6,7,8,9,10,11,12]. At the level of a polyclonal alloresponse in vivo, there is limited information about the role of the donor’s tissue-specific class I immunopeptidome in allorecognition and consequent immune responses that impact on graft survival

Methods

Results

Conclusion