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.