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ResearchIn-Press PreviewImmunologyTransplantation
Open Access | 10.1172/JCI179709
1Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
2Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
3Oncology, Novartis Institutes for Biomedical Research, Cambridge, United States of America
4Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States of America
5Transplantation Research Center, BWH, Harvard Medical School, Boston, United States of America
Find articles by Yokose, T. in: JCI | PubMed | Google Scholar
1Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
2Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
3Oncology, Novartis Institutes for Biomedical Research, Cambridge, United States of America
4Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States of America
5Transplantation Research Center, BWH, Harvard Medical School, Boston, United States of America
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1Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
2Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
3Oncology, Novartis Institutes for Biomedical Research, Cambridge, United States of America
4Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States of America
5Transplantation Research Center, BWH, Harvard Medical School, Boston, United States of America
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Rosales, I.
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1Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
2Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
3Oncology, Novartis Institutes for Biomedical Research, Cambridge, United States of America
4Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States of America
5Transplantation Research Center, BWH, Harvard Medical School, Boston, United States of America
Find articles by Guinn, M. in: JCI | PubMed | Google Scholar
1Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
2Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
3Oncology, Novartis Institutes for Biomedical Research, Cambridge, United States of America
4Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States of America
5Transplantation Research Center, BWH, Harvard Medical School, Boston, United States of America
Find articles by Liss, A. in: JCI | PubMed | Google Scholar
1Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
2Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
3Oncology, Novartis Institutes for Biomedical Research, Cambridge, United States of America
4Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States of America
5Transplantation Research Center, BWH, Harvard Medical School, Boston, United States of America
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1Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
2Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
3Oncology, Novartis Institutes for Biomedical Research, Cambridge, United States of America
4Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States of America
5Transplantation Research Center, BWH, Harvard Medical School, Boston, United States of America
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1Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
2Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
3Oncology, Novartis Institutes for Biomedical Research, Cambridge, United States of America
4Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States of America
5Transplantation Research Center, BWH, Harvard Medical School, Boston, United States of America
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1Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
2Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
3Oncology, Novartis Institutes for Biomedical Research, Cambridge, United States of America
4Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States of America
5Transplantation Research Center, BWH, Harvard Medical School, Boston, United States of America
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Azzi, J.
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1Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
2Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
3Oncology, Novartis Institutes for Biomedical Research, Cambridge, United States of America
4Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States of America
5Transplantation Research Center, BWH, Harvard Medical School, Boston, United States of America
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1Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
2Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
3Oncology, Novartis Institutes for Biomedical Research, Cambridge, United States of America
4Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States of America
5Transplantation Research Center, BWH, Harvard Medical School, Boston, United States of America
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1Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
2Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
3Oncology, Novartis Institutes for Biomedical Research, Cambridge, United States of America
4Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States of America
5Transplantation Research Center, BWH, Harvard Medical School, Boston, United States of America
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Madsen, J.
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1Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
2Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
3Oncology, Novartis Institutes for Biomedical Research, Cambridge, United States of America
4Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States of America
5Transplantation Research Center, BWH, Harvard Medical School, Boston, United States of America
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1Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
2Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
3Oncology, Novartis Institutes for Biomedical Research, Cambridge, United States of America
4Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States of America
5Transplantation Research Center, BWH, Harvard Medical School, Boston, United States of America
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Published June 18, 2024 - More info
Tolerance of mouse kidney allografts arises in grafts that develop regulatory Tertiary Lymphoid Organs (rTLOs). scRNAseq data and adoptive transfer of alloreactive T cells post-transplant showed that cytotoxic CD8+ T cells are reprogrammed within the accepted graft to an exhausted/regulatory-like phenotype mediated by IFN-γ. Establishment of rTLOs was required since adoptive transfer of alloreactive T cells prior to transplantation results in kidney allograft rejection. Despite intragraft CD8+ cells with a regulatory phenotype, they were not essential for the induction and maintenance of kidney allograft tolerance since renal allotransplantation into CD8 KO recipients resulted in acceptance and not rejection. Analysis of scRNAseq data from allograft kidneys and malignant tumors identified similar regulatory-like cell types within the T cell clusters and trajectory analysis showed that cytotoxic CD8+ T cells are reprogrammed into an exhausted/regulatory-like phenotype intratumorally. Induction of cytotoxic CD8+ T cell dysfunction of infiltrating cells appears to be a beneficial mechanistic pathway that protects the kidney allotransplant from rejection through a process we call “defensive tolerance.” This pathway has implications for our understanding of allotransplant tolerance and tumor resistance to host immunity.