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

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 and Hal Drakesmith ()
Additional contact information
Megan R. Teh: University of Oxford
Nancy Gudgeon: University of Birmingham
Joe N. Frost: University of Oxford
Linda V. Sinclair: University of Dundee
Alastair L. Smith: University of Oxford
Christopher L. Millington: University of Oxford
Barbara Kronsteiner: University of Oxford
Jennie Roberts: University of Birmingham
Bryan P. Marzullo: University of Birmingham
Hannah Murray: University of Oxford
Alexandra E. Preston: University of Oxford
Victoria Stavrou: University of Birmingham
Jan Rehwinkel: University of Oxford
Thomas A. Milne: University of Oxford
Daniel A. Tennant: University of Birmingham
Susanna J. Dunachie: University of Oxford
Andrew E. Armitage: University of Oxford
Sarah Dimeloe: University of Birmingham
Hal Drakesmith: University of Oxford

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60204-7

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