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The self-peptide repertoire plays a critical role in transplant tolerance induction
Eric T. Son, … , Nicole A. Mifsud, Alexandra F. Sharland
Eric T. Son, … , Nicole A. Mifsud, Alexandra F. Sharland
Published August 24, 2021
Citation Information: J Clin Invest. 2021;131(21):e146771. https://doi.org/10.1172/JCI146771.
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Research Article Immunology Article has an altmetric score of 44

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

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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.

Authors

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

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Figure 3

Expression of the SCT-Kb-KIIT construct in recipient hepatocytes prevents skin graft rejection mediated by alloreactive CD8+ T cells expressing the cognate TCR but does not induce tolerance in a polyclonal alloreactive population.

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Expression of the SCT-Kb-KIIT construct in recipient hepatocytes prevent...
(A) B10.BR-RAG mice were reconstituted with 1.0 × 104 to 2.5 × 105 Des-RAG lymphocytes, 3 days prior to receiving a Kb-bearing 178.3 skin graft. Some mice were also inoculated with AAV vectors. (B) 178.3 skin grafts survived indefinitely on immunodeficient B10.BR-RAG hosts. Progressive shortening in survival accompanied adoptive transfer of increasing cell numbers (Mantel-Cox log-rank test for trend: P < 0.0001, n = 6 per group). A dose of 50,000 cells was used subsequently. (C) Inoculation of reconstituted B10.BR-RAG recipients with AAV-SCT-Kb-KIIT resulted in indefinite graft survival, whereas treatment with AAV-SCT-Kb-SIIN offered no survival prolongation compared with that in untransduced recipients; median survival time (MST) of 18.5 days versus 20 days (P = 0.2, P = 0.0005 between mice receiving AAV-SCT-Kb-KIIT or AAV-SCT-Kb-SIIN, all groups n = 6). (D) Representative macroscopic images (from n = 6) demonstrate continued allograft survival in reconstituted B10.BR-RAG mice treated with AAV-SCT-Kb-KIIT but not other groups at 100 days after transplantation. (E) Representative IHC and H&E images showing syngeneic (B10.BR-RAG) and allogeneic (178.3) skin grafts 100 days posttransplant (scale bar: 100 μm). Skin transplants are morphologically normal, with persistent expression of H-2Kb in 178.3 grafts. (F) Immunosufficient B10.BR mice were inoculated with either AAV-HC-Kb, AAV-SCT-Kb-KIIT, or AAV-SCT-Kb-SIIN (n = 6 per group) or were not transduced (n = 9). Seven days after inoculation, the mice received 178.3 skin grafts. In these mice, expression of either SCT-Kb-KIIT or SCT-Kb-SIIN led to a modest increase in graft survival (MST of 25 days versus 17 days in no vector controls, P = 0.0007). However, only expression of H-2Kb loaded with the endogenous peptide repertoire was able to induce tolerance to 178.3 skin grafts. P = 0.0005 between B10.BR inoculated with AAV-HC-Kb and either AAV-SCT-Kb-KIIT or AAV-SCT-Kb-SIIN. (C and F) Mantel-Cox log-rank test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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