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

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 1

Donor MHCI–specific T cells remain hypofunctional following Lm infection.

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Donor MHCI–specific T cells remain hypofunctional following Lm infection...
(A) Experimental design. CD4+CD45.1+ TCR75/Rag–/– T cells (TCR75) were adoptively transferred into CD45.2+ B6 hosts either untransplanted and immunized with B/c donor splenocytes i.p. (UnTx+DST) to induce memory or prior to transplantation of a B/c heart (HTx) in the presence of αCD154 (day 0, day 7, day 14) and DST (day 0) to induce tolerance (Tol). A group of tolerant mice were infected with Lm on day 30 after transplantation (Tol+Lm). CD45.1+ TCR75 cells were harvested from the spleen and lymph nodes on days 35–37 after transplantation in all groups, enumerated, and subjected to bulk RNA-Seq. For recall proliferation, an equal number of harvested, sorted TCR75 cells were adoptively transferred into new congenic naive B6 hosts immunized with B/c splenocytes. Cells were enumerated from the spleen 7 days after in vivo rechallenge. (B) Fold change of TCR75 cells recovered from UnTx+DST (n = 13), Tol (n = 14), and Tol+Lm (n = 6, day 7 after Lm) mice, normalized to the number recovered in uninfected Tol animals. (C) Expansion in secondary hosts. Fold change of total TCR75 cells recovered from spleens of secondary hosts normalized to the cells recovered when TCR75 cells originated from Tol hosts prior to adoptive transfer. UnTx+DST (n = 14), Tol (n = 15), Tol+Lm (n = 8). (D) Principal component (PC) analysis of RNA-Seq. Gene expression comparison between naive TCR75 cells (day 0, n = 6), and memory TCR75 (UnTx+DST day 35, n = 3) or tolerant TCR75 cells from uninfected (Tol day 35, n = 5) or Tol+Lm analyzed day 5 after infection (n = 4). Statistical comparisons were performed with 1-way ANOVA with Bonferroni’s correction for multiple pairwise comparisons. **P < 0.01, ***P < 0.001, ****P < 0.0001.