Lipid metabolism drives dietary effects on T cell ferroptosis and immunity - Nature

All of the data supporting the findings of this study are available from the corresponding author. RNA-sequencing and scRNA-seq data described in the article have been deposited in the EMBL-EBI database and are accessible via accession number E-MTAB-16107 (bulk RNA-seq) and E-MTAB-16518 (scRNA-seq). Publicly available normalized and batch-adjusted RNA-sequencing data were obtained from GSE137122 (mouse TFH cells and non-TFH cells post-immunization). Source data are provided with this paper.

No new algorithms were developed for this Article. Processed data and analysis code are available from the corresponding author.

• Matsushita, M. et al. T cell lipid peroxidation induces ferroptosis and prevents immunity to infection. J. Exp. Med. 212, 555–568 (2015).Article CAS PubMed PubMed Central Google Scholar
• Yao, Y. et al. Selenium–GPX4 axis protects follicular helper T cells from ferroptosis. Nat. Immunol. 22, 1127–1139 (2021).Article CAS PubMed Google Scholar
• Xu, C. et al. The glutathione peroxidase Gpx4 prevents lipid peroxidation and ferroptosis to sustain Treg cell activation and suppression of antitumor immunity. Cell Rep. 35, 109235 (2021).Article CAS PubMed Google Scholar
• Ma, X. et al. CD36-mediated ferroptosis dampens intratumoral CD8+ T cell effector function and impairs their antitumor ability. Cell Metab. 33, 1001–1012.e5 (2021).Article CAS PubMed PubMed Central Google Scholar
• Wang, Y. et al. The kinase complex mTORC2 promotes the longevity of virus-specific memory CD4+ T cells by preventing ferroptosis. Nat. Immunol. 23, 303–317 (2022).Article PubMed Google Scholar
• Xu, S. et al. Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors. Immunity 54, 1561–1577.e1567 (2021).Article CAS PubMed PubMed Central Google Scholar
• Doll, S. et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat. Chem. Biol. 13, 91–98 (2017).Article CAS PubMed Google Scholar
• Bouillet, P. et al. BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature 415, 922–926 (2002).Article ADS CAS PubMed Google Scholar
• Ashby, K. M. & Hogquist, K. A. A guide to thymic selection of T cells. Nat. Rev. Immunol. 24, 103–117 (2024).Article CAS PubMed Google Scholar
• Dixon, S. J. & Pratt, D. A. Ferroptosis: a flexible constellation of related biochemical mechanisms. Mol. Cell 83, 1030–1042 (2023).Article CAS PubMed PubMed Central Google Scholar
• Dixon, S. J. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060–1072 (2012).Article CAS PubMed PubMed Central Google Scholar
• Bersuker, K. et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature 575, 688–692 (2019).Article ADS CAS PubMed PubMed Central Google Scholar
• Beatty, A. et al. Ferroptotic cell death triggered by conjugated linolenic acids is mediated by ACSL1. Nat. Commun. 12, 2244 (2021).Article ADS CAS PubMed PubMed Central Google Scholar
• Ingold, I. et al. Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis. Cell 172, 409–422.e421 (2018).Article ADS CAS PubMed Google Scholar
• Aldrovandi, M., Fedorova, M. & Conrad, M. Juggling with lipids, a game of Russian roulette. Trends Endocrinol. Metab. 32, 463–473 (2021).Article CAS PubMed Google Scholar
• Stockwell, B. R. Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. Cell 185, 2401–2421 (2022).Article CAS PubMed PubMed Central Google Scholar
• Dixon, S. J. & Olzmann, J. A. The cell biology of ferroptosis. Nat. Rev. Mol. Cell Biol. 25, 424–442 (2024).Article CAS PubMed PubMed Central Google Scholar
• Tang, D., Chen, X., Kang, R. & Kroemer, G. Ferroptosis: molecular mechanisms and health implications. Cell Res. 31, 107–125 (2021).Article CAS PubMed Google Scholar
• Mallapaty, S. Loss of Australia’s largest lab animal supplier will leave ‘huge gap’. Nature https://doi.org/10.1038/d41586-021-01896-x (2021).
• Nielsen, F. H. The AIN-93 purified diets for laboratory rodents-the development of a landmark article in the Journal of Nutrition and its impact on health and disease research using rodent models. J. Nutr. 148, 1667–1670 (2018).Article PubMed Google Scholar
• Reeves, P. G., Nielsen, F. H. & Fahey, G. C. Jr. AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. J. Nutr. 123, 1939–1951 (1993).Article CAS PubMed Google Scholar
• NIH Specification: Open Formula Rat and Mouse Ration—18% Crude Protein Autoclavable (NIH-31). https://ors.od.nih.gov/sr/dvr/Documents/nih31-137j2004.pdf (2004).
• Berndt, C. et al. Ferroptosis in health and disease. Redox Biol. 75, 103211 (2024).Article CAS PubMed PubMed Central Google Scholar
• Rooks, M. G. & Garrett, W. S. Gut microbiota, metabolites and host immunity. Nat. Rev. Immunol. 16, 341–352 (2016).Article CAS PubMed PubMed Central Google Scholar
• Wang, G. et al. Butyrate dictates ferroptosis sensitivity through FFAR2–mTOR signaling. Cell Death Dis. 14, 292 (2023).Article PubMed PubMed Central Google Scholar
• Liang, D., Minikes, A. M. & Jiang, X. Ferroptosis at the intersection of lipid metabolism and cellular signaling. Mol. Cell 82, 2215–2227 (2022).Article CAS PubMed PubMed Central Google Scholar
• Upadhyayula, P. S. et al. Dietary restriction of cysteine and methionine sensitizes gliomas to ferroptosis and induces alterations in energetic metabolism. Nat. Commun. 14, 1187 (2023).Article ADS CAS PubMed PubMed Central Google Scholar
• Zhang, S. et al. Double-edge sword roles of iron in driving energy production versus instigating ferroptosis. Cell Death Dis. 13, 40 (2022).Article CAS PubMed PubMed Central Google Scholar
• Philpott, C. C., Patel, S. J. & Protchenko, O. Management versus miscues in the cytosolic labile iron pool: The varied functions of iron chaperones. Biochim. Biophys. Acta 1867, 118830 (2020).Article CAS Google Scholar
• Tallima, H. & El Ridi, R. Arachidonic acid: physiological roles and potential health benefits - A review. J. Adv. Res. 11, 33–41 (2018).Article CAS PubMed Google Scholar
• Fujino, T., Kang, M. J., Suzuki, H., Iijima, H. & Yamamoto, T. Molecular characterization and expression of rat acyl-CoA synthetase 3. J. Biol. Chem. 271, 16748–16752 (1996).Article CAS PubMed Google Scholar
• Kang, M. J. et al. A novel arachidonate-preferring acyl-CoA synthetase is present in steroidogenic cells of the rat adrenal, ovary, and testis. Proc. Natl Acad. Sci. USA 94, 2880–2884 (1997).Article ADS CAS PubMed PubMed Central Google Scholar
• Magtanong, L. et al. Exogenous monounsaturated fatty acids promote a ferroptosis-resistant cell state. Cell Chem. Biol. 26, 420–432.e429 (2019).Article CAS PubMed PubMed Central Google Scholar
• Roelands, J. et al. Long-chain acyl-CoA synthetase 1 role in sepsis and immunity: perspectives from a parallel review of public transcriptome datasets and of the literature. Front. Immunol. 10, 2410 (2019).Article CAS PubMed PubMed Central Google Scholar
• Pope, L. E. & Dixon, S. J. Regulation of ferroptosis by lipid metabolism. Trends Cell Biol. 33, 1077–1087 (2023).Article CAS PubMed PubMed Central Google Scholar
• Liu, W. et al. Ferroptosis inducer improves the efficacy of oncolytic virus-mediated cancer immunotherapy. Biomedicines 10, 1425 (2022).Article CAS PubMed PubMed Central Google Scholar
• Gonzalez-Figueroa, P. et al. Follicular regulatory T cells produce neuritin to regulate B cells. Cell 184, 1775–1789.e1719 (2021).Article CAS PubMed Google Scholar
• Zou, Y. et al. Plasticity of ether lipids promotes ferroptosis susceptibility and evasion. Nature 585, 603–608 (2020).Article ADS CAS PubMed PubMed Central Google Scholar
• Qiu, B. et al. Phospholipids with two polyunsaturated fatty acyl tails promote ferroptosis. Cell 187, 1177–1190.e1118 (2024).Article CAS PubMed PubMed Central Google Scholar
• Morgan, P. K. et al. A lipid atlas of human and mouse immune cells provides insights into ferroptosis susceptibility. Nat. Cell Biol. 26, 645–659 (2024).Article CAS PubMed Google Scholar
• Brassard, P. et al. Modulation of T-cell signalling by non-esterified fatty acids. Prostaglandins Leukot. Essent. Fatty Acids 77, 337–343 (2007).Article CAS PubMed Google Scholar
• Xu, L., Davis, T. A. & Porter, N. A. Rate constants for peroxidation of polyunsaturated fatty acids and sterols in solution and in liposomes. J. Am. Chem. Soc. 131, 13037–13044 (2009).Article ADS CAS PubMed PubMed Central Google Scholar
• Yin, H., Xu, L. & Porter, N. A. Free radical lipid peroxidation: mechanisms and analysis. Chem. Rev. 111, 5944–5972 (2011).Article CAS PubMed Google Scholar
• Mika, A. & Sledzinski, T. Alterations of specific lipid groups in serum of obese humans: a review. Obes Rev. 18, 247–272 (2017).Article CAS PubMed Google Scholar
• Leong, Y. A. et al. CXCR5+ follicular cytotoxic T cells control viral infection in B cell follicles. Nat. Immunol. 17, 1187–1196 (2016).Article CAS PubMed Google Scholar
• Chen, Z. et al. Heparan sulfate regulates IL-21 bioavailability and signal strength that control germinal center B cell selection and differentiation. Sci. Immunol. 8, eadd1728 (2023).Article CAS PubMed Google Scholar
• He, J. et al. Low-dose interleukin-2 treatment selectively modulates CD4+ T cell subsets in patients with systemic lupus erythematosus. Nat. Med. 22, 991–993 (2016).Article CAS PubMed Google Scholar
• Nussing, S. et al. Efficient CRISPR/Cas9 gene editing in uncultured naive mouse T cells for in vivo studies. J. Immunol. 204, 2308–2315 (2020).Article CAS PubMed Google Scholar
• Drijvers, J. M. et al. Pharmacologic screening identifies metabolic vulnerabilities of CD8+ T cells. Cancer Immunol. Res. 9, 184–199 (2021).Article CAS PubMed Google Scholar
• Jung, Y. H. & Bu, S. Y. Suppression of long chain acyl-CoA synthetase blocks intracellular fatty acid flux and glucose uptake in skeletal myotubes. Biochim. Biophys. Acta 1865, 158678 (2020).Article CAS Google Scholar
• Killion, E. A. et al. A role for long-chain acyl-CoA synthetase-4 (ACSL4) in diet-induced phospholipid remodeling and obesity-associated adipocyte dysfunction. Mol. Metab. 9, 43–56 (2018).Article CAS PubMed PubMed Central Google Scholar
• Sun, C. et al. Spatially resolved multi-omics highlights cell-specific metabolic remodeling and interactions in gastric cancer. Nat. Commun. 14, 2692 (2023).Article ADS CAS PubMed PubMed Central Google Scholar
• Stoessel, D. et al. Metabolomics and lipidomics reveal perturbation of sphingolipid metabolism by a novel anti-trypanosomal 3-(oxazolo[4,5-b]pyridine-2-yl)anilide. Metabolomics 12, 126 (2016).Article Google Scholar
• Wolf, F. A., Angerer, P. & Theis, F. J. SCANPY: large-scale single-cell gene expression data analysis. Genome Biol. 19, 15 (2018).Article PubMed PubMed Central Google Scholar
• Scialdone, A. et al. Computational assignment of cell-cycle stage from single-cell transcriptome data. Methods 85, 54–61 (2015).Article CAS PubMed Google Scholar
• Suo, C. et al. Dandelion uses the single-cell adaptive immune receptor repertoire to explore lymphocyte developmental origins. Nat. Biotechnol. 42, 40–51 (2024).Article CAS PubMed Google Scholar

Article CAS PubMed PubMed Central Google Scholar

Yao, Y. et al. Selenium–GPX4 axis protects follicular helper T cells from ferroptosis. Nat. Immunol. 22, 1127–1139 (2021).

Xu, C. et al. The glutathione peroxidase Gpx4 prevents lipid peroxidation and ferroptosis to sustain Treg cell activation and suppression of antitumor immunity. Cell Rep. 35, 109235 (2021).

Ma, X. et al. CD36-mediated ferroptosis dampens intratumoral CD8+ T cell effector function and impairs their antitumor ability. Cell Metab. 33, 1001–1012.e5 (2021).

Wang, Y. et al. The kinase complex mTORC2 promotes the longevity of virus-specific memory CD4+ T cells by preventing ferroptosis. Nat. Immunol. 23, 303–317 (2022).

Xu, S. et al. Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors. Immunity 54, 1561–1577.e1567 (2021).

Doll, S. et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat. Chem. Biol. 13, 91–98 (2017).

Bouillet, P. et al. BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature 415, 922–926 (2002).

Article ADS CAS PubMed Google Scholar

Ashby, K. M. & Hogquist, K. A. A guide to thymic selection of T cells. Nat. Rev. Immunol. 24, 103–117 (2024).

Dixon, S. J. & Pratt, D. A. Ferroptosis: a flexible constellation of related biochemical mechanisms. Mol. Cell 83, 1030–1042 (2023).

Dixon, S. J. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060–1072 (2012).

Bersuker, K. et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature 575, 688–692 (2019).

Article ADS CAS PubMed PubMed Central Google Scholar

Beatty, A. et al. Ferroptotic cell death triggered by conjugated linolenic acids is mediated by ACSL1. Nat. Commun. 12, 2244 (2021).

Ingold, I. et al. Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis. Cell 172, 409–422.e421 (2018).

Aldrovandi, M., Fedorova, M. & Conrad, M. Juggling with lipids, a game of Russian roulette. Trends Endocrinol. Metab. 32, 463–473 (2021).

Stockwell, B. R. Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. Cell 185, 2401–2421 (2022).

Dixon, S. J. & Olzmann, J. A. The cell biology of ferroptosis. Nat. Rev. Mol. Cell Biol. 25, 424–442 (2024).

Tang, D., Chen, X., Kang, R. & Kroemer, G. Ferroptosis: molecular mechanisms and health implications. Cell Res. 31, 107–125 (2021).

Mallapaty, S. Loss of Australia’s largest lab animal supplier will leave ‘huge gap’. Nature https://doi.org/10.1038/d41586-021-01896-x (2021).

Nielsen, F. H. The AIN-93 purified diets for laboratory rodents-the development of a landmark article in the Journal of Nutrition and its impact on health and disease research using rodent models. J. Nutr. 148, 1667–1670 (2018).

Reeves, P. G., Nielsen, F. H. & Fahey, G. C. Jr. AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. J. Nutr. 123, 1939–1951 (1993).

NIH Specification: Open Formula Rat and Mouse Ration—18% Crude Protein Autoclavable (NIH-31). https://ors.od.nih.gov/sr/dvr/Documents/nih31-137j2004.pdf (2004).

Berndt, C. et al. Ferroptosis in health and disease. Redox Biol. 75, 103211 (2024).

Rooks, M. G. & Garrett, W. S. Gut microbiota, metabolites and host immunity. Nat. Rev. Immunol. 16, 341–352 (2016).

Wang, G. et al. Butyrate dictates ferroptosis sensitivity through FFAR2–mTOR signaling. Cell Death Dis. 14, 292 (2023).

Article PubMed PubMed Central Google Scholar

Liang, D., Minikes, A. M. & Jiang, X. Ferroptosis at the intersection of lipid metabolism and cellular signaling. Mol. Cell 82, 2215–2227 (2022).

Upadhyayula, P. S. et al. Dietary restriction of cysteine and methionine sensitizes gliomas to ferroptosis and induces alterations in energetic metabolism. Nat. Commun. 14, 1187 (2023).

Zhang, S. et al. Double-edge sword roles of iron in driving energy production versus instigating ferroptosis. Cell Death Dis. 13, 40 (2022).

Philpott, C. C., Patel, S. J. & Protchenko, O. Management versus miscues in the cytosolic labile iron pool: The varied functions of iron chaperones. Biochim. Biophys. Acta 1867, 118830 (2020).

Tallima, H. & El Ridi, R. Arachidonic acid: physiological roles and potential health benefits - A review. J. Adv. Res. 11, 33–41 (2018).

Fujino, T., Kang, M. J., Suzuki, H., Iijima, H. & Yamamoto, T. Molecular characterization and expression of rat acyl-CoA synthetase 3. J. Biol. Chem. 271, 16748–16752 (1996).

Kang, M. J. et al. A novel arachidonate-preferring acyl-CoA synthetase is present in steroidogenic cells of the rat adrenal, ovary, and testis. Proc. Natl Acad. Sci. USA 94, 2880–2884 (1997).

Magtanong, L. et al. Exogenous monounsaturated fatty acids promote a ferroptosis-resistant cell state. Cell Chem. Biol. 26, 420–432.e429 (2019).

Roelands, J. et al. Long-chain acyl-CoA synthetase 1 role in sepsis and immunity: perspectives from a parallel review of public transcriptome datasets and of the literature. Front. Immunol. 10, 2410 (2019).