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Heterogeneity in allospecific T cell function in transplant-tolerant hosts determines susceptibility to rejection following infection
Christine M. McIntosh, … , Anita S. Chong, Maria-Luisa Alegre
Christine M. McIntosh, … , Anita S. Chong, Maria-Luisa Alegre
Published September 7, 2023
Citation Information: J Clin Invest. 2023;133(21):e168465. https://doi.org/10.1172/JCI168465.
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Research Article Article has an altmetric score of 15

Heterogeneity in allospecific T cell function in transplant-tolerant hosts determines susceptibility to rejection following infection

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Abstract

Even when successfully induced, immunological tolerance to solid organs remains vulnerable to inflammatory insults, which can trigger rejection. In a mouse model of cardiac allograft tolerance in which infection with Listeria monocytogenes (Lm) precipitates rejection of previously accepted grafts, we showed that recipient CD4+ TCR75 cells reactive to a donor MHC class I–derived peptide become hypofunctional if the allograft is accepted for more than 3 weeks. Paradoxically, infection-induced transplant rejection was not associated with transcriptional or functional reinvigoration of TCR75 cells. We hypothesized that there is heterogeneity in the level of dysfunction of different allospecific T cells, depending on duration of their cognate antigen expression. Unlike CD4+ TCR75 cells, CD4+ TEa cells specific for a peptide derived from donor MHC class II, an alloantigen whose expression declines after transplantation but remains inducible in settings of inflammation, retained function in tolerant mice and expanded during Lm-induced rejection. Repeated injections of alloantigens drove hypofunction in TEa cells and rendered grafts resistant to Lm-dependent rejection. Our results uncover a functional heterogeneity in allospecific T cells of distinct specificities after tolerance induction and reveal a strategy to defunctionalize a greater repertoire of allospecific T cells, thereby mitigating a critical vulnerability of tolerance.

Authors

Christine M. McIntosh, Jennifer B. Allocco, Peter Wang, Michelle L. McKeague, Alexandra Cassano, Ying Wang, Stephen Z. Xie, Grace Hynes, Ricardo Mora-Cartín, Domenic Abbondanza, Luqiu Chen, Husain Sattar, Dengping Yin, Zheng J. Zhang, Anita S. Chong, Maria-Luisa Alegre

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Figure 5

Increased presentation of donor MHCII–derived peptides can be induced in settings of Lm infection at the maintenance phase of tolerance.

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Increased presentation of donor MHCII–derived peptides can be induced in...
(A) Gating strategy for endothelial cells from heart allografts. (B) I-Ad/I-Ed expression on graft-isolated CD45–CD31+Kd+ endothelial cells. Native represents B/c hearts directly taken ex vivo. AR represents hearts from untreated mice at day 8 after transplantation. Tol grafts were analyzed between days 1 and 90 after transplantation+CoB. Tol+Lm mice were infected day 30 after transplantation+CoB, and grafts were evaluated on days 4–8 after infection. Native (n = 8), AR (n = 4), days 1–2 (n = 3), days 8–9 (n = 3), days 16–18 (n = 3), days 35–90 (n = 16), Tol+Lm d-8 p.i. (n = 15). For comparison between groups, results were normalized to levels of expression of MHCII in endothelial cells from tolerant grafts at days 35–90 after transplantation (dotted line). (C) B6 mice transplanted with B/c hearts and treated with CoB were infected or not with Lm on day 30 after transplantation. Splenocytes were analyzed 4–8 days later for expression of Eα:I-Ab on CD11c+ gated events and normalized to the average expression on DCs from naive mice in each independent experiment. Tol (n = 6), Tol+Lm (n = 9). (D) Experimental model. Some B6 mice received a B/c heart graft, and tolerance was induced with CoB (Tol HTx). Thirty-five days after transplantation, a subset of these mice were infected with Lm (Tol HTx+Lm). Four days after infection, all mice were adoptively transferred with CFSE-labeled naive TEa cells. Control untransplanted mice received TEa cells at the same time as B/c splenocyte immunization (UnTx+DST). All TEa cells were recovered on day 4 after adoptive transfer. (E) Percentages of CD45.1+ TEa cells that proliferated on day 4 after adoptive transfer. UnTx+DST (n = 5), Tol (n = 4), Tol+Lm (n = 7). Data were analyzed by 1-way ANOVA with Bonferroni’s correction for multiple pairwise comparisons (B and E) or unpaired 2-tailed t test (C). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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