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.
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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.
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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.