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Publications

Journal Article Epublish

PubMed: 40541943 DOI: 10.1038/s41467-025-60204-7

Iron deficiency causes aspartate-sensitive dysfunction in CD8 + T cells.

Nat Commun 16(1):5355

Authors: Megan R Teh, Nancy Gudgeon, Joe N Frost, Linda V Sinclair, Alastair L Smith, Christopher L Millington, Barbara Kronsteiner, Jennie Roberts, Bryan P Marzullo, Hannah Murray, Alexandra E Preston, Victoria Stavrou, Jan Rehwinkel, Thomas A Milne, Daniel A Tennant, Susanna J Dunachie, Andrew E Armitage, Sarah Dimeloe, Hal Drakesmith

Affiliations

  • MRC Translational Immune Discovery Unit, Radcliffe Department of Medicine, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
  • CeMM-Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.
  • MRC Translational Immune Discovery Unit, Radcliffe Department of Medicine, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
  • Division of Cell Signalling and Immunology, University of Dundee, Dundee, UK.
  • MRC Molecular Haematology Unit, Radcliffe Department of Medicine, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
  • Nuffield Department of Clinical Medicine, NDM Centre for Global Health Research, University of Oxford, Oxford, UK.
  • School of Medical Sciences, College of Medicine and Health, Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
  • Mahidol-Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand.
  • MRC Translational Immune Discovery Unit, Radcliffe Department of Medicine, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.

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 + 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 + 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 + 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 + T cell function, providing mechanistic insight into the basis for immune impairment during iron deficiency.

MeSH

Cells, Mitochondria, Iron Deficiencies