ACC1 determines memory potential of individual CD4+ T cells by regulating de novo fatty acid biosynthesis

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. ACC1 is a rate-limiting enzyme during fatty acid biosynthesis. Here the authors describe how loss of ACC1 enhances CD4+ memory T cell formation and improves outcome in a murine model of parasite infection, indicating that lipid biosynthesis directs cell-fate determination during the generation of memory T cells.