Mucosal-associated invariant T cells recognize a tumor-derived metabolite in the DNA synthesis pathway - Summary - MDSpire

Mucosal-associated invariant T cells recognize a tumor-derived metabolite in the DNA synthesis pathway

  • By

  • Yanqi Xue

  • Yuka Yamada

  • Rikako Suzuki

  • Brenda Luong

  • Shotaro Fujii

  • Keisuke Nakata

  • Masatomo Takahashi

  • Yoshihiro Izumi

  • Chihiro Fukui

  • Ryosuke Takasaki

  • Francois Legoux

  • Shinsuke Inuki

  • Daisuke Motooka

  • Emi Ito

  • Bridget L. Stocker

  • Mattie S. M. Timmer

  • Takashi Shimizu

  • Yasumasa Matsuoka

  • Jun’ichi Mano

  • Koji Tamada

  • Makoto Furutani-Seiki

  • Kei Sakamoto

  • Koh-Hei Sonoda

  • Olivier Lantz

  • Sho Yamasaki

  • Kensuke Shibata

  • June 24, 2026

  • 0 min

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Objective:

To identify tumor-derived ligands recognized by mucosal-associated invariant T (MAIT) cells, specifically focusing on 5-formyl tetrahydrofolate (5-formyl THF).

Approach:
  • Ligand Identification: The study demonstrated that 5-formyl THF, an intermediate of the folate metabolism pathway, activates mouse MAIT cells in a T cell receptor (TCR)-dependent manner.
  • Genetic Manipulation: Genetic deletion of the enzyme amino methyltransferase (Amt) in tumors impaired MAIT cell activation, while Amt overexpression enhanced it.
  • TCR Reactivity Testing: Mouse MAIT TCRs were introduced to primary T cells from MAIT cell-deficient mice to confirm reactivity to 5-formyl THF.
  • Human Clonotype Identification: Single-cell TCR sequencing analysis identified a 5-formyl THF-reactive MAIT cell clonotype in humans.
Key Findings:
  • 5-formyl THF is the first tumor-derived ligand recognized by MAIT cells in both humans and mice.
  • Activation of MAIT cells by 5-formyl THF is weaker compared to the potent agonist 5-OP-RU.
  • The enzyme Amt is crucial for the generation of 5-formyl THF from tumor cells.
Interpretation:

The findings indicate a novel interaction between MAIT cells and tumor-derived metabolites, specifically 5-formyl THF.

Limitations:
  • The functional relevance of the 5-formyl THF pathway in vivo remains to be determined.
Conclusion:

This study identifies 5-formyl THF as a significant ligand for MAIT cells, contributing to the understanding of MAIT cell biology in the tumor microenvironment.

Original Source(s)

Mucosal-associated invariant T cells recognize a tumor-derived metabolite in the DNA synthesis pathway

  • by Yanqi Xue, Yuka Yamada, Rikako Suzuki, Brenda Luong, Shotaro Fujii, Keisuke Nakata, Masatomo Takahashi, Yoshihiro Izumi, Chihiro Fukui, Ryosuke Takasaki, Francois Legoux, Shinsuke Inuki, Daisuke Motooka, Emi Ito, Bridget L. Stocker, Mattie S. M. Timmer, Takashi Shimizu, Yasumasa Matsuoka, Jun’ichi Mano, Koji Tamada, Makoto Furutani-Seiki, Kei Sakamoto, Koh-Hei Sonoda, Olivier Lantz, Sho Yamasaki, Kensuke Shibata

  • June 24, 2026

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