MYC-Driven Glycolysis in TNFRSF4+ CD4+ T Cells Underlies Heightened Rejection Susceptibility of Cardiac vs. Renal Allografts
Abstract
BACKGROUND: Cardiac allografts show poorer long-term survival and decreased tolerance compared to renal allografts, but the underlying mechanisms remain unclear. METHODS AND RESULTS: We established heterotopic heart and kidney allotransplantation models in Bama miniature pigs. Single-cell RNA sequencing (scRNA-seq) was performed to analyze normal heart/kidney tissues and allografts. Transcription factor analysis focused on T-cell subsets, with key findings validated using clinical human heart tissues (normal vs. acute rejection) and a mouse heart transplantation model (to test MYC inhibition). T/NK (TNK) subsets in cardiac allografts exhibited higher expression of genes linked to immune system activation, mature B-cell differentiation, and immune memory. The TNFRSF4+ CD4+ T-cell subset was selectively expanded in cardiac allografts (but reduced in renal allografts) during acute rejection, with transcriptional analysis identifying MYC as a master regulator of glycolysis-related genes in this subset. In the mouse heart transplant model, inhibition of MYC (via 10058-F4) reduced the proportion of TNFRSF4+ CD4+ T cells and significantly prolonged cardiac allograft survival. CONCLUSIONS: Our study identified a MYC-driven, glycolysis-dependent expansion of TNFRSF4+ CD4+ T cells as a key mechanism contributing to the heightened rejection susceptibility of cardiac allografts (vs. renal allografts). These findings provide a rationale for developing cardiac-targeted immunosuppressive strategies.
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BibTeX
@article{li2026mycdriven,
title = {{MYC-Driven Glycolysis in TNFRSF4+ CD4+ T Cells Underlies Heightened Rejection Susceptibility of Cardiac vs. Renal Allografts}},
author = {Peiyuan Li and Yuan Chang and Xiaofei Zhu and Xiao Chen and Xiumeng Hua and Yixuan Sheng and Ningning Zhang and Qian Zhao and Kai Xing and Xingchao Du and Mengda Xu and Jiangping Song},
journal = {Circulation Journal},
year = {2026},
month = oct,
doi = {10.1253/circj.cj-25-0880},
url = {https://www.jstage.jst.go.jp/article/circj/90/11/90_CJ-25-0880/_article},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - MYC-Driven Glycolysis in TNFRSF4+ CD4+ T Cells Underlies Heightened Rejection Susceptibility of Cardiac vs. Renal Allografts
AU - Peiyuan Li
AU - Yuan Chang
AU - Xiaofei Zhu
AU - Xiao Chen
AU - Xiumeng Hua
AU - Yixuan Sheng
AU - Ningning Zhang
AU - Qian Zhao
AU - Kai Xing
AU - Xingchao Du
AU - Mengda Xu
AU - Jiangping Song
PY - 2026
DA - 2026/10/23
JO - Circulation Journal
DO - 10.1253/circj.cj-25-0880
UR - https://www.jstage.jst.go.jp/article/circj/90/11/90_CJ-25-0880/_article
AB - BACKGROUND: Cardiac allografts show poorer long-term survival and decreased tolerance compared to renal allografts, but the underlying mechanisms remain unclear. METHODS AND RESULTS: We established heterotopic heart and kidney allotransplantation models in Bama miniature pigs. Single-cell RNA sequencing (scRNA-seq) was performed to analyze normal heart/kidney tissues and allografts. Transcription factor analysis focused on T-cell subsets, with key findings validated using clinical human heart tissues (normal vs. acute rejection) and a mouse heart transplantation model (to test MYC inhibition). T/NK (TNK) subsets in cardiac allografts exhibited higher expression of genes linked to immune system activation, mature B-cell differentiation, and immune memory. The TNFRSF4+ CD4+ T-cell subset was selectively expanded in cardiac allografts (but reduced in renal allografts) during acute rejection, with transcriptional analysis identifying MYC as a master regulator of glycolysis-related genes in this subset. In the mouse heart transplant model, inhibition of MYC (via 10058-F4) reduced the proportion of TNFRSF4+ CD4+ T cells and significantly prolonged cardiac allograft survival. CONCLUSIONS: Our study identified a MYC-driven, glycolysis-dependent expansion of TNFRSF4+ CD4+ T cells as a key mechanism contributing to the heightened rejection susceptibility of cardiac allografts (vs. renal allografts). These findings provide a rationale for developing cardiac-targeted immunosuppressive strategies.
SN - 1347-4820
SN - 1346-9843
ER -