L-Phenylalanine is a metabolic checkpoint of human Th2 cells
Year: 2025
Type: article
Abstract: After the primary response, circulating memory CD4 + 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 + T, memory CD4 + T, and Th2 cells, but not in Th1, Th17, or Treg cells. L-phenylalanine also restrains proliferation of memory CD4 + 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.
Source: Cell Reports Medicine
Authors: Abhijeet J. Kulkarni, Juan Rodriguez-Coira, Nino Stocker, Urszula Radzikowska, Antonio J. García-Cívico, María Isabel Delgado Dolset, Nuria Contreras, Inés Jardón Parages, Vanesa Saiz Sanchez, Pilar Serrano, Elena Izquierdo, Cristina Gomez-Casado, Javier Sanchez-Solares, Carmela Pablo-Torres, David Obeso, Carmen Moreno-Aguilar, Maria Luisa Espinazo, Andrzej Eljaszewicz, Jana Koch, Katja Baerenfaller, Anja Heider, Ge Tan, Damir Zhakparov, Maria M. Escribese, Berta Ruiz-Leon, Cezmi A. Akdis, Rafael J. Argüello, Domingo Barber, Alma Villaseñor, Milena Sokolowska
Institutions: University of Zurich, Universidad San Pablo CEU, Instituto Maimónides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofía, University of Córdoba, Medical University of Białystok, University Clinical Hospital In Bialystok, SIB Swiss Institute of Bioinformatics, University of Augsburg, ETH Zurich, Functional Genomics Center Zurich, CK-CARE, Centre National de la Recherche Scientifique, Inserm, Aix-Marseille Université, Centre d’Immunologie de Marseille-Luminy
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,620
Funders: National Science Foundation, Fundación Mutua Madrileña, Banco Santander, Comunidad de Madrid, European Commission, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Federación Española de Enfermedades Raras, Universität Zürich, European Academy of Allergy and Clinical Immunology, Universidad San Pablo - CEU, Instituto de Salud Carlos III, European Regional Development Fund, Fundación Universitaria San Pablo CEU
Awards: Patología alérgica grave: Validación de biomarcadores y nuevas estrategias de intervención en alergia (VABMAN), G2670821590, G3267476915, G3567434945, G4135802076, G502912864, G5600313180, G7238463878, Immunometabolism in asthma, allergy and immune tolerance., Determinantes Genéticos de alergia Grave (GEDESAL), G8658329250, G8690818240, G871842226, G880118091, Nuevo abordaje terapéutico en pacientes con alergia a polen de olivo de fenotipo grave
OpenAlex ID: W4416701790