Ruddy, David, Piquet, Michelle, Takahiro, Yokose, Andrew, Liss and Alessandro Alessandrini, Alessandrini (2024) Defensive tolerance results in dysfunction of infiltrating cytotoxic CD8+ T cells through in situ reprogramming. The Journal of clinical investigation : JCI. ISSN 1558-8238; 0021-9738

Abstract

Tolerance of mouse kidney allografts arises in grafts that develop regulatory Tertiary
Lymphoid Organs (rTLOs). scRNAseq data and adoptive transfer of alloreactive T cells posttransplant
show that cytotoxic CD8+ T cells are reprogrammed within the accepted graft to an
exhausted/regulatory-like phenotype. Establishment of rTLOs is 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. Analysis of scRNAseq data from allograft kidneys
and malignant tumors identified similar regulatory-like cell types within the T cell clusters.
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 novel pathway has implications for our understanding of
allotransplant tolerance and tumor resistance to host immunity.

Item Type:	Article
Date Deposited:	10 Jul 2024 00:46
Last Modified:	10 Jul 2024 00:46
URI:	https://oak.novartis.com/id/eprint/52836