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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.
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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

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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

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Figure 4

Increased IFN-γ expression and production within the T cell population in accepted kidney allografts, but FGL2 and CD8+ cells are not needed for the induction and maintenance of accepted kidney allografts.

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Increased IFN-γ expression and production within the T cell population i...
(A) Density plots of Ifng+ cells in total cells in accepted kidney allografts at each time point. (B) Violin plots and dot plots show levels and percentages of Ifng expression in T cell subset in accepted kidney allografts at each time point. (C) Bar graph shows ELISPOT analysis of IFN-γ production in T cells obtained from accepted kidney allograft and recipient’s spleen at 4 weeks after transplantation. Data are represented as mean ± SD, compared by 2-way ANOVA test. (D) Graft survival curve after kidney transplantation into IFN-γ–KO (n = 3) or WT (n = 3) mice (P = 0.007). (E) Graft survival curve after kidney transplantation into Fgl2-KO (n = 6) or WT (n = 6) mice (P = 0.138). (F) Line graph of serum levels of creatinine (Cr) and blood urea nitrogen (BUN) in long-term-surviving Fgl2-KO recipients (n = 3). Data represent the mean ± SEM. (G) Graft survival curve after kidney transplantation into CD8-KO (n = 5) and WT (n = 5) mice. (H) Graft survival curve after heart transplantation into CD8-KO (n = 3) and WT (n = 3) mice (P = 0.432). (I and J) Pathological findings of kidney allografts obtained from CD8-KO recipients. (I) H&E staining shows perivascular rTLO formation. (J) Immunohistochemistry of CD8 staining shows the absence of CD8+ cell infiltration in kidney allografts taken from CD8-KO recipients. (K) Graft survival curve after kidney transplantation into PD-1–KO (n = 5) and WT (n = 5) mice (P = 0.002). (L) H&E staining of kidney allografts obtained from PD-1–KO mice shows signs of rejection. Statistical significance was determined by log-rank test (D, E, H, and K). Scale bars: 100 μm (I, J, and L).

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