1. Dysfunction of infiltrating cytotoxic [CD8.sup.+] T cells within the graft promotes murine kidney allotransplant tolerance
- Author
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Yokose, Takahiro, Szuter, Edward S., Rosales, Ivy, Guinn, Michael T., Liss, Andrew S., Baba, Taisuke, Ruddy, David A., Piquet, Michelle, Azzi, Jamil, Cosimi, A. Benedict, Russell, Paul S., Madsen, Joren C., Colvin, Robert B., and Alessandrini, Alessandro
- Subjects
CD8 lymphocytes -- Health aspects -- Genetic aspects ,RNA sequencing -- Methods ,Lymphoid tissue -- Health aspects -- Genetic aspects - Abstract
Tolerance of mouse kidney allografts arises in grafts that develop regulatory tertiary lymphoid organs (rTLOs). Singlecell RNA-seq (scRNA-seq) data and adoptive transfer of alloreactive T cells after transplantation showed that cytotoxic [CD8.sup.+] T cells are reprogrammed within the accepted graft to an exhausted/regulatory-like phenotype mediated by IFN-[gamma]. 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.sup.+] 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.sup.+] T cells are reprogrammed into an exhausted/regulatory-like phenotype intratumorally. Induction of cytotoxic [CD8.sup.+] 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., Introduction Traditionally, inflammatory and regulatory immune responses after transplantation were thought to be primarily generated in secondary lymphoid organs (1, 2). However, it has been increasingly recognized that both deleterious [...]
- Published
- 2024
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