Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Dysfunction of infiltrating cytotoxic CD8+ T cells within the graft promotes murine kidney allotransplant tolerance
Takahiro Yokose, … , Robert B. Colvin, Alessandro Alessandrini
Takahiro Yokose, … , Robert B. Colvin, Alessandro Alessandrini
Published June 18, 2024
Citation Information: J Clin Invest. 2024;134(16):e179709. https://doi.org/10.1172/JCI179709.
View: Text | PDF
Research Article Immunology Article has an altmetric score of 9

Dysfunction of infiltrating cytotoxic CD8+ T cells within the graft promotes murine kidney allotransplant tolerance

  • Text
  • PDF
Abstract

Tolerance of mouse kidney allografts arises in grafts that develop regulatory tertiary lymphoid organs (rTLOs). Single-cell RNA-seq (scRNA-seq) data and adoptive transfer of alloreactive T cells after transplantation 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 because adoptive transfer of alloreactive T cells prior to transplantation results in kidney allograft rejection. Despite the presence of 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 scRNA-seq 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.

Authors

Takahiro Yokose, Edward S. Szuter, Ivy Rosales, Michael T. Guinn, Andrew S. Liss, Taisuke Baba, David A. Ruddy, Michelle Piquet, Jamil Azzi, A. Benedict Cosimi, Paul S. Russell, Joren C. Madsen, Robert B. Colvin, Alessandro Alessandrini

×

Figure 1

scRNA-seq and flow cytometry show that CD8+ T cells constitute the significant population of infiltrating immune cells in the early stages of kidney allograft acceptance.

Options: View larger image (or click on image) Download as PowerPoint
scRNA-seq and flow cytometry show that CD8+ T cells constitute the signi...
(A–C) UMAP plots (A and C) and bar graphs (B and C) of immune cell populations at each time point in scRNA-seq data of accepted kidney allografts (A and B) and rejecting kidney allografts at 1 week after transplantation (C). (D) Flow cytometric analysis of CD8+ T cells in accepted kidney allografts at 1 week and 25 weeks after transplantation. Data are represented as mean ± SEM, compared by 2-tailed Student’s t test. (E–H) Histopathological findings in accepted kidney allografts at 1 week (E) and 6 weeks (F) after transplantation and rejecting kidney allografts at 1 week (G and H) after transplantation. (E, F, and H) Immunohistochemistry of CD8 staining. (G) H&E staining. Scale bars: 100 μm.

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

Sign up for email alerts

Posted by 14 X users
7 readers on Mendeley
See more details