Defective respiration and one-carbon metabolism contribute to impaired naïve T cell activation in aged mice.

TitleDefective respiration and one-carbon metabolism contribute to impaired naïve T cell activation in aged mice.
Publication TypeJournal Article
Year of Publication2018
AuthorsRon-Harel, N, Notarangelo, G, Ghergurovich, JM, Paulo, JA, Sage, PT, Santos, D, F Satterstrom, K, Gygi, SP, Rabinowitz, JD, Sharpe, AH, Haigis, MC
JournalProc Natl Acad Sci U S A
Volume115
Issue52
Pagination13347-13352
Date Published2018 12 26
ISSN1091-6490
KeywordsAge Factors, Animals, Carbon, CD4-Positive T-Lymphocytes, Female, Immunity, Cellular, Immunity, Innate, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Mitochondria, Organelle Biogenesis, Respiration, T-Lymphocytes
Abstract

T cell-mediated immune responses are compromised in aged individuals, leading to increased morbidity and reduced response to vaccination. While cellular metabolism tightly regulates T cell activation and function, metabolic reprogramming in aged T cells has not been thoroughly studied. Here, we report a systematic analysis of metabolism during young versus aged naïve T cell activation. We observed a decrease in the number and activation of naïve T cells isolated from aged mice. While young T cells demonstrated robust mitochondrial biogenesis and respiration upon activation, aged T cells generated smaller mitochondria with lower respiratory capacity. Using quantitative proteomics, we defined the aged T cell proteome and discovered a specific deficit in the induction of enzymes of one-carbon metabolism. The activation of aged naïve T cells was enhanced by addition of products of one-carbon metabolism (formate and glycine). These studies define mechanisms of skewed metabolic remodeling in aged T cells and provide evidence that modulation of metabolism has the potential to promote immune function in aged individuals.

DOI10.1073/pnas.1804149115
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID30530686
PubMed Central IDPMC6310842
Grant ListR01 CA213062 / CA / NCI NIH HHS / United States
R01 GM067945 / GM / NIGMS NIH HHS / United States