Immunological memory is central to adaptive immunity and protection from disease. Changing metabolic demands as antigen-specific T cells transition from effector to memory cells have been well documented, but the cell-specific pathways and molecules that govern this transition are poorly defined. Here we show that genetic deletion of ACC1, a rate-limiting enzyme in fatty acid biosynthesis, enhances the formation of CD4+ T memory cells. ACC1-deficient effector helper T (Th) cells have similar metabolic signatures to wild-type memory Th cells, and expression of the gene encoding ACC1, Acaca, was inversely correlated with a memory gene signature in individual cells. Inhibition of ACC1 function enhances memory T cell formation during parasite infection in mice. Using single-cell analyses we identify a memory precursor–enriched population (CCR7hiCD137lo) present during early differentiation of effector CD4+ T cells. Our data indicate that fatty acid metabolism directs cell fate determination during the generation of memory CD4+ T cells.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $8.67 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
All data presented in this article are available in the main and supplementary figures, or upon request from corresponding authors. RNA-seq, microarray and single-cell rtPCR data in this manuscript are available in the Gene Expression Omnibus database (http://www.ncbi.nlm.nih.gov/geo) under accession number GSE122863 (SuperSeries). All data that support the findings of this study are available from the corresponding author upon reasonable request.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Chang, J. T., Wherry, E. J. & Goldrath, A. W. Molecular regulation of effector and memory T cell differentiation. Nat. Immunol. 15, 1104–1115 (2014).
Pulendran, B. & Ahmed, R. Immunological mechanisms of vaccination. Nat. Immunol. 12, 509–517 (2011).
Sallusto, F., Lanzavecchia, A., Araki, K. & Ahmed, R. From vaccines to memory and back. Immunity 33, 451–463 (2010).
Maus, M. V. et al. Adoptive immunotherapy for cancer or viruses. Annu. Rev. Immunol. 32, 189–225 (2014).
Vanneman, M. & Dranoff, G. Combining immunotherapy and targeted therapies in cancer treatment. Nat. Rev. Cancer 12, 237–251 (2012).
Nakayama, T. et al. Th2 cells in health and disease. Annu. Rev. Immunol. 35, 53–84 (2017).
Williams, M. A. & Bevan, M. J. Effector and memory CTL differentiation. Annu. Rev. Immunol. 25, 171–192 (2007).
Endo, Y., Hirahara, K., Yagi, R., Tumes, D. J. & Nakayama, T. Pathogenic memory type Th2 cells in allergic inflammation. Trends Immunol. 35, 69–78 (2014).
Stockinger, B., Bourgeois, C. & Kassiotis, G. CD4+ memory T cells: functional differentiation and homeostasis. Immunol. Rev. 211, 39–48 (2006).
Jameson, S. C. & Masopust, D. Diversity in T cell memory: an embarrassment of riches. Immunity 31, 859–871 (2009).
Pearce, E. L. et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460, 103–107 (2009).
O’Sullivan, D. et al. Memory CD8(+) T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development. Immunity 41, 75–88 (2014).
Wang, R. & Green, D. R. Metabolic checkpoints in activated T cells. Nat. Immunol. 13, 907–915 (2012).
MacIver, N. J., Michalek, R. D. & Rathmell, J. C. Metabolic regulation of T lymphocytes. Annu. Rev. Immunol. 31, 259–283 (2013).
Pearce, E. L. & Pearce, E. J. Metabolic pathways in immune cell activation and quiescence. Immunity 38, 633–643 (2013).
Cui, G. et al. IL-7-induced glycerol transport and tag synthesis promotes memory CD8+ T cell longevity. Cell 161, 750–761 (2015).
Zeng, H. et al. mTORC1 couples immune signals and metabolic programming to establish T(reg)-cell function. Nature 499, 485–490 (2013).
Okoye, I. et al. T cell metabolism. The protein LEM promotes CD8(+) T cell immunity through effects on mitochondrial respiration. Science 348, 995–1001 (2015).
Araki, K. et al. mTOR regulates memory CD8 T-cell differentiation. Nature 460, 108–112 (2009).
Bantug, G. R., Galluzzi, L., Kroemer, G. & Hess, C. The spectrum of T cell metabolism in health and disease. Nat. Rev. Immunol. 18, 19–34 (2018).
Sukumar, M. et al. Inhibiting glycolytic metabolism enhances CD8+T cell memory and antitumor function. J. Clin. Invest. 123, 4479–4488 (2013).
Kidani, Y. et al. Sterol regulatory element-binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity. Nat. Immunol. 14, 489–499 (2013).
Angela, M. et al. Fatty acid metabolic reprogramming via mTOR-mediated inductions of PPARgamma directs early activation of T cells. Nat. Commun. 7, 13683 (2016).
Pan, Y. et al. Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism. Nature 543, 252–256 (2017).
Endo, Y. et al. Obesity drives th17 cell differentiation by inducing the lipid metabolic kinase, ACC1. Cell Rep. 12, 1042–1055 (2015).
Berod, L. et al. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat. Med. 20, 1327–1333 (2014).
Endo, Y., Yokote, K. & Nakayama, T. The obesity-related pathology and Th17 cells. Cell. Mol. Life Sci. 74, 1231–1245 (2017).
Best, J. A. et al. Transcriptional insights into the CD8(+) T cell response to infection and memory T cell formation. Nat. Immunol. 14, 404–412 (2013).
Lee, J. et al. Regulator of fatty acid metabolism, acetyl coenzyme a carboxylase 1, controls T cell immunity. J. Immunol. 192, 3190–3199 (2014).
Mao, J. et al. Liver-specific deletion of acetyl-CoA carboxylase 1 reduces hepatic triglyceride accumulation without affecting glucose homeostasis. Proc. Natl Acad. Sci. USA 103, 8552–8557 (2006).
Barnden, M. J., Allison, J., Heath, W. R. & Carbone, F. R. Defective TCR expression in transgenic mice constructed using cDNA-based alpha- and beta-chain genes under the control of heterologous regulatory elements. Immunol. Cell Biol. 76, 34–40 (1998).
Fulda, S., Galluzzi, L. & Kroemer, G. Targeting mitochondria for cancer therapy. Nat. Rev. Drug. Discov. 9, 447–464 (2010).
Sukumar, M. et al. Mitochondrial membrane potential identifies cells with enhanced stemness for cellular therapy. Cell. Metab. 23, 63–76 (2016).
van der Windt, G. J. et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 36, 68–78 (2012).
Arsenio, J. et al. Early specification of CD8+T lymphocyte fates during adaptive immunity revealed by single-cell gene-expression analyses. Nat. Immunol. 15, 365–372 (2014).
Ishizuka, I. E. et al. Single-cell analysis defines the divergence between the innate lymphoid cell lineage and lymphoid tissue-inducer cell lineage. Nat. Immunol. 17, 269–276 (2016).
Rutishauser, R. L. et al. Transcriptional repressor Blimp-1 promotes CD8(+) T cell terminal differentiation and represses the acquisition of central memory T cell properties. Immunity 31, 296–308 (2009).
Xin, A. et al. A molecular threshold for effector CD8(+ T cell differentiation controlled by transcription factors Blimp-1 and T-bet. Nat. Immunol. 17, 422–432 (2016).
Murphy, K. M., Heimberger, A. B. & Loh, D. Y. Induction by antigen of intrathymic apoptosis of CD4+CD8+TCRlo thymocytes in vivo. Science 250, 1720–1723 (1990).
Endo, Y. et al. The interleukin-33-p38 kinase axis confers memory T helper 2 cell pathogenicity in the airway. Immunity 42, 294–308 (2015).
We thank S.J. Wakil (Baylor College of Medicine) for providing the Acacafl/fl mice and M. Papadopoulos for critical reading and providing valuable suggestions on the manuscript. We also thank K. Sugaya and M. Kato for their excellent technical assistance. This work was supported by the Global COE Program (Global Center for Education and Research in Immune System Regulation and Treatment) and by grants from the Ministry of Education, Culture, Sports, Science and Technology (MEXT Japan) (grants-in-aid for Scientific Research [S] 26221305, [B] 21390147, and [C] 15K08522, Young Scientists [A] 16H06224, [B] 24790461, and 26870172, Challenging Research (Pioneering) 18H05375, grant-in-aid for Scientific Research on Innovative Areas (research in a proposed research area) 16H01352, 18H04665), AMED-CREST, AMED (P18gm1210003, JP16gm0410009), Practical Research Project for Allergic Diseases and Immunology from AMED (JP17ek0410030), the Ministry of Health, Labor and Welfare, the Astellas Foundation for Research on Metabolic Disorders, Ono Medical Research Foundation, Kanae Foundation for the Promotion of Medical Science, and Takeda Science Foundation.