2. Academic Validation
  3. Early methionine availability attenuates T cell exhaustion

Early methionine availability attenuates T cell exhaustion

  • Nat Immunol. 2025 Aug;26(8):1384-1396. doi: 10.1038/s41590-025-02223-6.
Piyush Sharma 1,  Ao Guo 2 3,  Suresh Poudel 2,  Emilio Boada-Romero 2,  Katherine C Verbist 2,  Gustavo Palacios 2,  Kalyan Immadisetty 4 5,  Mark J Chen 2 5,  Dalia Haydar 6,  Ashutosh Mishra 7,  Junmin Peng 8,  M Madan Babu 4,  Giedre Krenciute 6,  Evan S Glazer 9,  Douglas R Green 10
Affiliations

Affiliations

  • 1 Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. piyush.sharma@stjude.org.
  • 2 Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 3 Department of Oncology, National Key Laboratory of Immune Response and Immunotherapy, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  • 4 Department of Structural Biology, Center of Excellence in Data Driven Discovery, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 5 Department of Laboratory Medicine, Cleveland Clinic, Cleveland, OH, USA.
  • 6 Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 7 Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 8 Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 9 Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, USA.
  • 10 Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. douglas.green@stjude.org.
PMID: 40702340 DOI: 10.1038/s41590-025-02223-6
Abstract

T cell receptor (TCR) activation is regulated in many ways, including niche-specific nutrient availability. Here we investigated how methionine (Met) availability and TCR signaling interplay during the earliest events of T cell activation affect subsequent cell fate. Limiting Met during the initial 30 min of TCR engagement increased CA2+ influx, NFAT1 (encoded by Nfatc2) activation and promoter occupancy, leading to T cell exhaustion. We identified changes in the protein arginine methylome during initial TCR engagement and identified an arginine methylation of the CA2+-activated potassium transporter KCa3.1, which regulates CA2+-mediated NFAT1 signaling for optimal activation. Ablation of KCa3.1 arginine methylation increased NFAT1 nuclear localization, rendering T cells dysfunctional in mouse tumor and Infection models. Furthermore, acute, early Met supplementation reduced nuclear NFAT1 in tumor-infiltrating T cells and augmented antitumor activity. These findings identify a metabolic event early after T cell activation that affects cell fate.

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