# Targeting the Mapk13‐Tcf1‐Slc7a5 Axis via One‐Carbon Metabolic Regulation to Prevent Chronic Allograft Vasculopathy

## TL;DR

This study identifies a metabolic pathway involving Mapk13, Tcf1, and Slc7a5 that helps harmful T cells survive, leading to chronic rejection of transplanted organs, and suggests targeting this pathway could improve graft survival.

## Contribution

The study reveals a novel metabolic-epigenetic axis involving Mapk13, Tcf1, and Slc7a5 that sustains stem-like CD4+ T cells in chronic allograft vasculopathy.

## Key findings

- Mapk13 phosphorylates Tcf1, enabling Slc7a5 activation and methionine uptake in stem-like CD4+ T cells.
- Disrupting the Mapk13-Tcf1-Slc7a5 axis reduces T cell stemness and prevents chronic allograft vasculopathy in mice.
- Limiting one-carbon metabolism suppresses pathogenic T cells and improves graft survival.

## 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.

This study emphasizes the role of the Mapk13‐Tcf1‐Slc7a5‐methionine metabolism axis in stem‐like CD4+ T cells. Moreover, it uncovers the mechanism through which limiting one‐carbon metabolism in CD4+ stem‐like T cells suppresses the tide of chronic allograft vasculopathy, offering potential targets to promote long‐term graft survival.