MYC-Driven Glycolysis in TNFRSF4+ CD4+ T Cells Underlies Heightened Rejection Susceptibility of Cardiac vs. Renal Allografts.

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.