Iron deficiency causes aspartate-sensitive dysfunction in CD8+ T cells
Issued Date
2025-12-01
Resource Type
eISSN
20411723
Scopus ID
2-s2.0-105008685488
Journal Title
Nature Communications
Volume
16
Issue
1
Rights Holder(s)
SCOPUS
Bibliographic Citation
Nature Communications Vol.16 No.1 (2025)
Suggested Citation
Teh M.R., Gudgeon N., Frost J.N., Sinclair L.V., Smith A.L., Millington C.L., Kronsteiner B., Roberts J., Marzullo B.P., Murray H., Preston A.E., Stavrou V., Rehwinkel J., Milne T.A., Tennant D.A., Dunachie S.J., Armitage A.E., Dimeloe S., Drakesmith H. Iron deficiency causes aspartate-sensitive dysfunction in CD8+ T cells. Nature Communications Vol.16 No.1 (2025). doi:10.1038/s41467-025-60204-7 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/110975
Title
Iron deficiency causes aspartate-sensitive dysfunction in CD8+ T cells
Author's Affiliation
University of Birmingham
University of Oxford Medical Sciences Division
University of Dundee
Nuffield Department of Medicine
University of Birmingham, College of Medical and Dental Sciences
Mahidol Oxford Tropical Medicine Research Unit
Research Center for Molecular Medicine of the Austrian Academy of Sciences
University of Oxford Medical Sciences Division
University of Dundee
Nuffield Department of Medicine
University of Birmingham, College of Medical and Dental Sciences
Mahidol Oxford Tropical Medicine Research Unit
Research Center for Molecular Medicine of the Austrian Academy of Sciences
Corresponding Author(s)
Other Contributor(s)
Abstract
Iron is an irreplaceable co-factor for metabolism. Iron deficiency affects >1 billion people and decreased iron availability impairs immunity. Nevertheless, how iron deprivation impacts immune cell function remains poorly characterised. We interrogate how physiologically low iron availability affects CD8<sup>+</sup> T cell metabolism and function, using multi-omic and metabolic labelling approaches. Iron limitation does not substantially alter initial post-activation increases in cell size and CD25 upregulation. However, low iron profoundly stalls proliferation (without influencing cell viability), alters histone methylation status, gene expression, and disrupts mitochondrial membrane potential. Glucose and glutamine metabolism in the TCA cycle is limited and partially reverses to a reductive trajectory. Previous studies identified mitochondria-derived aspartate as crucial for proliferation of transformed cells. Despite aberrant TCA cycling, aspartate is increased in stalled iron deficient CD8<sup>+</sup> T cells but is not utilised for nucleotide synthesis, likely due to trapping within depolarised mitochondria. Exogenous aspartate markedly rescues expansion and some functions of severely iron-deficient CD8<sup>+</sup> T cells. Overall, iron scarcity creates a mitochondrial-located metabolic bottleneck, which is bypassed by supplying inhibited biochemical processes with aspartate. These findings reveal molecular consequences of iron deficiency for CD8<sup>+</sup> T cell function, providing mechanistic insight into the basis for immune impairment during iron deficiency.