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

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

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 2

Intragraft gene expression within the CD8+ T cell clusters in accepted kidney allografts shows changes from a cytotoxic to an exhausted/regulatory-like phenotype.

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Intragraft gene expression within the CD8+ T cell clusters in accepted k...
(A and B) UMAP plots of CD8+ T cell cluster subsets at each time point in accepted kidney allografts (A) and rejecting kidney allografts at 1 week (B). (C and E) Violin plots of cytotoxic (red) and exhaustion/regulatory (green) genes in CD8+ T cell clusters in accepted kidney allografts (C) and accepted recipient’s spleen (E). The vertical axis indicates log-ranked gene expression levels. Mean expression levels are indicated as black points. (D) Density plot of CD8a+Fgl2+Il2rb+ cells in accepted kidney allografts at 3 weeks after transplantation. (F) Bar graph shows ELISPOT analysis of IFN-γ production in T cells and CD8+ T cells obtained from accepted kidney allograft and recipient’s spleen at 24 weeks after transplantation. Data are represented as mean ± SD, compared by 2-way ANOVA test. (G) Violin plot and dot plot of cytotoxic (red) and exhaustion/regulatory (green) genes in CD8+ T cell clusters, comparing rejecting grafts at 1 week and accepted kidney allografts at 1 and 3 weeks. The black dot in violin plots indicates the mean value of expression levels. (H) Heatmap of top differentially expressed genes in CD8+ T cell clusters at each time point in accepted kidney allografts.