Mucosal-associated invariant T cells recognize a tumor-derived metabolite in the DNA synthesis pathway
Abstract
Mucosal-associated invariant T (MAIT) cells recognize metabolite-derived ligands, but the identity of such ligands in the context of cancer remains poorly defined. Herein, we demonstrate that the tumor-derived metabolite 5-formyl tetrahydrofolate (5-formyl THF), which is an intermediate of the folate metabolism pathway, induces T cell receptor (TCR)-dependent activation of mouse mucosal-associated invariant T (MAIT) cells. The activity was weaker than that of a potent MAIT cell agonist 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU). Amino methyltransferase (Amt), an enzyme that is necessary for the generation of 5-formyl THF from tumor cells, was essential for the activation of mouse MAIT cells. Genetic deletion of Amt in the tumor resulted in impaired activation of mouse MAIT cells. In contrast, Amt overexpression in the tumor led to an enhancement in the agonistic activity of the MAIT cells. The introduction of mouse MAIT TCRs to primary T cells from MAIT cell-deficient mice also conferred reactivity to 5-formyl THF. Using single-cell TCR sequencing analysis, a 5-formyl THF-reactive MAIT cell clonotype was identified in humans. These results demonstrate that 5-formyl THF is the first tumor-derived ligand recognized by MAIT cells in both humans and mice. However, the functional relevance of this pathway in vivo remains to be determined.
Related
- Commentary: acupuncture-associated gastric mucosal repair and the EGF–EGFR-related signaling network: evidence, limitations, and prospects
- Subspace Image Synthesis for Style-Invariant Object Recognition
- Resident mucosal programmes in colon cancer: organ-associated formation and remodelling of the immune niche
- A mucosal barrier injury related six gene transcriptomic signature associated with ulcerative colitis using machine learning and public transcriptomic data
- Kynurenic acid attenuates experimental allergic rhinitis: Evidence for AhR-associated regulation of mucosal immune homeostasis
BibTeX
@article{xue2026mucosalassociated,
title = {{Mucosal-associated invariant T cells recognize a tumor-derived metabolite in the DNA synthesis pathway}},
author = {Yanqi Xue and Yuka Yamada and Rikako Suzuki and Brenda Luong and Shotaro Fujii and Keisuke Nakata and Masatomo Takahashi and Yoshihiro Izumi and Chihiro Fukui and Ryosuke Takasaki and François Legoux and Shinsuke Inuki and Daisuke Motooka and Emi Ito and Bridget L. Stocker and Mattie S. M. Timmer and Takashi Shimizu and Yasumasa Matsuoka and Jun’ichi Mano and Koji Tamada and Makoto Furutani-Seiki and Kei Sakamoto and Koh-Hei Sonoda and Olivier Lantz and Sho Yamasaki and Kensuke Shibata},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1797918},
url = {https://hal.science/hal-05674917v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Mucosal-associated invariant T cells recognize a tumor-derived metabolite in the DNA synthesis pathway
AU - Yanqi Xue
AU - Yuka Yamada
AU - Rikako Suzuki
AU - Brenda Luong
AU - Shotaro Fujii
AU - Keisuke Nakata
AU - Masatomo Takahashi
AU - Yoshihiro Izumi
AU - Chihiro Fukui
AU - Ryosuke Takasaki
AU - François Legoux
AU - Shinsuke Inuki
AU - Daisuke Motooka
AU - Emi Ito
AU - Bridget L. Stocker
AU - Mattie S. M. Timmer
AU - Takashi Shimizu
AU - Yasumasa Matsuoka
AU - Jun’ichi Mano
AU - Koji Tamada
AU - Makoto Furutani-Seiki
AU - Kei Sakamoto
AU - Koh-Hei Sonoda
AU - Olivier Lantz
AU - Sho Yamasaki
AU - Kensuke Shibata
PY - 2026
DA - 2026/10/14
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1797918
UR - https://hal.science/hal-05674917v1
AB - Mucosal-associated invariant T (MAIT) cells recognize metabolite-derived ligands, but the identity of such ligands in the context of cancer remains poorly defined. Herein, we demonstrate that the tumor-derived metabolite 5-formyl tetrahydrofolate (5-formyl THF), which is an intermediate of the folate metabolism pathway, induces T cell receptor (TCR)-dependent activation of mouse mucosal-associated invariant T (MAIT) cells. The activity was weaker than that of a potent MAIT cell agonist 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU). Amino methyltransferase (Amt), an enzyme that is necessary for the generation of 5-formyl THF from tumor cells, was essential for the activation of mouse MAIT cells. Genetic deletion of Amt in the tumor resulted in impaired activation of mouse MAIT cells. In contrast, Amt overexpression in the tumor led to an enhancement in the agonistic activity of the MAIT cells. The introduction of mouse MAIT TCRs to primary T cells from MAIT cell-deficient mice also conferred reactivity to 5-formyl THF. Using single-cell TCR sequencing analysis, a 5-formyl THF-reactive MAIT cell clonotype was identified in humans. These results demonstrate that 5-formyl THF is the first tumor-derived ligand recognized by MAIT cells in both humans and mice. However, the functional relevance of this pathway in vivo remains to be determined.
SN - 1664-3224
SN - 1664-3224
ER -