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Updated: Jun 24, 2026
Mouse Model of Alloimmune-induced Vascular Rejection and Transplant Arteriosclerosis
Published on: May 17, 2015
Targeting the Mapk13-Tcf1-Slc7a5 Axis via One-Carbon Metabolic Regulation to Prevent Chronic Allograft Vasculopathy
Wang Yi1,2,3, Di Wu4, Jing Liu1,2,3
1Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Abstract:
Chronic allograft vasculopathy (CAV) is driven in part by stem-like CD4+ T cells, but how these cells sustain their progenitor programs during chronic rejection remains unclear. Here, a metabolic-epigenetic axis is identified in which Mapk13 phosphorylates Tcf1 at T289, enabling Tcf1 to activate the amino acid transporter Slc7a5 and enhance methionine uptake. This rewires one-carbon metabolism and increases H3K4me3 enrichment at the Tcf7 locus, thereby maintaining stem-like CD4+ T cells within rejecting grafts. Disruption of this circuit-via genetic deletion of Mapk13 or Slc7a5, or through dietary methionine restriction-reduces Tcf1+ CD4+ T cell stemness and prevents CAV in mouse models. These findings reveal the Mapk13-Tcf1-Slc7a5 axis as a critical metabolic dependency of pathogenic T cells and highlight one-carbon metabolism as a promising target to promote long-term graft survival.
Insights
A newly discovered metabolic pathway involving Mapk13, Tcf1, and Slc7a5 sustains stem-like CD4+ T cells in chronic allograft vasculopathy (CAV). Targeting this axis or methionine uptake may improve long-term transplant survival.
Area of Science:
- Immunology
- Metabolic pathways
- Epigenetics
Background:
- Chronic allograft vasculopathy (CAV) is a major cause of organ transplant failure.
- Stem-like CD4+ T cells contribute to CAV pathogenesis.
- The mechanisms sustaining these cells during chronic rejection are not fully understood.
Purpose of the Study:
- To elucidate the metabolic and epigenetic mechanisms maintaining stem-like CD4+ T cells in CAV.
- To identify potential therapeutic targets for preventing CAV.
Main Methods:
- Investigated the role of Mapk13, Tcf1, and Slc7a5 in a mouse model of CAV.
- Utilized genetic deletion, dietary methionine restriction, and metabolic/epigenetic analyses.
- Assessed T cell stemness and CAV progression.
Main Results:
- Identified a metabolic-epigenetic axis: Mapk13 phosphorylates Tcf1, enhancing Slc7a5 and methionine uptake.
- This process increases H3K4me3 at the Tcf7 locus, maintaining CD4+ T cell stemness.
- Disrupting this axis (via genetic deletion or methionine restriction) reduced T cell stemness and prevented CAV in mice.
Conclusions:
- The Mapk13-Tcf1-Slc7a5 axis is crucial for sustaining pathogenic T cells in CAV.
- One-carbon metabolism represents a promising therapeutic target for enhancing long-term graft survival.
