L-Phenylalanine is a metabolic checkpoint of human Th2 cells
After the primary response, circulating memory CD4<sup>+</sup>T effector and T regulatory (Treg) cells regulate recall responses, typically impaired in allergy. We discovered distinct metabolomes of these cells in humans, differentially enriched in phenylalanine-related metabolites. Energy metabolism assessment in in vitro and ex vivo single-cell analyses revealed that increased intracellular L-phenylalanine boosts glycolysis while limiting oxidative phosphorylation (OXPHOS) in CD4<sup>+</sup>T, memory CD4<sup>+</sup>T, and Th2 cells, but not in Th1, Th17, or Treg cells. L-phenylalanine also restrains proliferation of memory CD4<sup>+</sup>T, Th2, and Th17 cells in an IL4I1-dependent manner and limits Th2 differentiation via inhibition of STAT6 and mechanistic target of rapamycin (mTOR) signaling. RNA sequencing, metabolomics, flow cytometry, and proteomics, validated both in vitro and across patient cohorts, revealed impaired LAT1-dependent transport of L-phenylalanine into Th2 cells in allergy, with increased intracellular processing accompanied by expansion of pathogenic Th2 cells. Thus, our study identifies L-phenylalanine as a checkpoint in Th2 cell development, energy metabolism, and function.
Authors
- Victoria Sánchez (ORCID: https://orcid.org/0009-0000-3580-8198)
- David Obeso (ORCID: https://orcid.org/0000-0001-7875-7327)
- Jana Koch (ORCID: https://orcid.org/0000-0002-7552-6088)
- Rafael J. Argüello (ORCID: https://orcid.org/0000-0001-9785-3883)
- Ge Tan (ORCID: https://orcid.org/0000-0003-0026-8739)
- Milena Sokołowska (ORCID: https://orcid.org/0000-0001-9710-6685)
- N. Contreras (ORCID: https://orcid.org/0000-0002-5724-7288)
- María Isabel Delgado Dolset (ORCID: https://orcid.org/0000-0001-7924-5454)
- Berta Ruiz (ORCID: https://orcid.org/0000-0001-5556-4127)
- Alma Villaseñor (ORCID: https://orcid.org/0000-0002-6652-2739)
- Urszula Radzikowska (ORCID: https://orcid.org/0000-0002-7341-9764)
- Pilar Serrano (ORCID: https://orcid.org/0000-0002-9810-2421)
- Juan Rodríguez‐Coira (ORCID: https://orcid.org/0000-0003-0517-7078)
- Domingo Barber (ORCID: https://orcid.org/0000-0002-5488-5700)
- Carmela Pablo‐Torres (ORCID: https://orcid.org/0000-0003-2861-5763)
- Javier Sánchez‐Solares (ORCID: https://orcid.org/0000-0001-8202-7175)
- Cezmi A. Akdiş (ORCID: https://orcid.org/0000-0001-8020-019X)
- Katja Baerenfaller (ORCID: https://orcid.org/0000-0002-1904-9440)
- C Moreno (ORCID: https://orcid.org/0000-0001-7273-911X)
- Andrzej Eljaszewicz (ORCID: https://orcid.org/0000-0002-8980-1474)
- Anja Heider (ORCID: https://orcid.org/0000-0002-3448-4125)
- Nino Stocker (ORCID: https://orcid.org/0000-0003-3200-8982)
- María Marta Escribese (ORCID: https://orcid.org/0000-0001-5057-5150)
- Elena Izquierdo (ORCID: https://orcid.org/0000-0002-3355-2798)
- Cristina Gómez‐Casado (ORCID: https://orcid.org/0000-0002-7707-6367)
- Damir Zhakparov (ORCID: https://orcid.org/0000-0001-7175-0843)
- Antonio J García-Cívico (ORCID: https://orcid.org/0009-0009-1082-2626)
- Abhijeet J Kulkarni (ORCID: https://orcid.org/0009-0008-4299-7706)
- Inés Jardón Parages
- Maria Luisa Espinazo
Institutions
- Universidad San Pablo CEU (ES)
- SIB Swiss Institute of Bioinformatics (CH)
- Centre National de la Recherche Scientifique (FR)
- Medical University of Białystok (PL)
- Inserm (FR)
- University of Zurich (CH)
- Aix-Marseille Université (FR)
- Instituto Maimónides de Investigación Biomédica de Córdoba (ES)
- Swiss Institute for Art Research (CH)
- CK-CARE (CH)
- Centre d’Immunologie de Marseille-Luminy (FR)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-11-26
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102466
- Citations
- 1
- Primary Topic
- Mast cells and histamine
- Type
- article
- Field-Weighted Citation Impact
- 0.80