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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 3

T cells specific for donor MHCII retain function following induction of transplantation tolerance.

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T cells specific for donor MHCII retain function following induction of ...
(A) Experimental design. (B, C, and D) UMAP plots (B) generated from 2,000 live TCR-Tg Tconvs per condition. TCR75 (left) and TEa (center) cells shown separately and together (right). FlowSOM (far right) identified distinct clusters, distinguishing between naive (populations 2 and 3), Tol TCR75 cells (populations 0, 1, 5), and Tol TEa (population 4) cells. Radar plots showing the relative expression of markers (as percentage of maximal expression) between naive (C) or Tol (D) TCR-Tg cells. n = 3–4 per group. (E and F) Percentage of TCR-Tg Tconvs expressing CD73hiFR4hi (E) or MFI of PD1 (F). Results were pooled from 2–4 independent experiments. E: Naive TCR75 (n = 4), AR TCR75 (n = 5), Tol TCR75 (n = 6), naive TEa (n = 5), AR TEa (n = 6), Tol TEa (n = 12). F: naive TCR75 (n = 8), AR TCR75 (n = 11), Tol TCR75 (n = 14), naive TEa (n = 5), AR TEa (n = 5), Tol TEa (n = 5). Data are represented as mean ± SEM. Significance not depicted in panel E: naive TCR75 versus Tol TCR75 (****), naive TEa vs Tol TEa (*). Significance not depicted in panel F: naive TCR75 versus Tol TCR75 (**), naive TEa versus Tol TEa (*), naive TEa versus AR TEa (**). (G) Representative flow plots. TCR75 cells were seeded at the time of B/c splenocyte immunization (DST) or B/c heart transplantation+CoB treatment (Tol). Splenocytes were harvested on day >30 and plated overnight with anti-CD3/CD28. CD4+CD45.1+ gated events were analyzed for the percentage of IFN-γ+ and/or TNF+ cells. (H and I) Percentages of TCR-Tg T IFN-γ (H) or TNF (I) post anti-CD3/CD28 restimulation. Results were pooled from 3 independent experiments. Each data point represents a sample pooled from 1–5 mice (mean ± SEM). AR TCR75 (n = 8), Tol TCR75 (n = 10), AR TEa (n = 8), Tol TEa (n = 11). (J) Splenic TCR-Tg T cells enumerated 5 days post-DST immunization of secondary hosts. Results normalized to the average cell recovery of TCR-Tg T cells originating from AR primary hosts, set to 1 for each independent experiment (mean ± SEM). AR TCR75 (n = 3), Tol TCR75 (n = 5), AR TEa (n = 7), Tol TEa (n = 7). Data were analyzed by 1-way ANOVA with Bonferroni’s correction for multiple pairwise comparisons (E and F). Data comparing TCR75 or TEa cells in AR versus Tol (H–J) were analyzed by unpaired 2-tailed t test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 for all data

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

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