Persistence and plasticity of bona fide T follicular memory cells

T follicular helper (TFH) cells regulate antibody production. Following infection or vaccination, effector TFH cells give rise to long-lived memory TFH cells. The survival requirements, lineage flexibility and impact of TFH memory cells have not been fully elucidated. In this study we determined that TFH memory cells persist to at least 400 days after infection while T cells with a central memory phenotype are largely absent. Single cell RNA sequencing reveals that TFH memory cells express many genes associated with stemness and self-renewal; reconstruction of a developmental trajectory suggests that TFH memory cells occur earlier in pseudotime, giving rise to other Th cell subsets in a linear fashion. Surprisingly, TFH memory cells concurrently express a distinct metabolic signature similar to trained immune cells, including elevated expression of mTOR, HIF-1 and cAMP regulated genes. TFH memory cell survival is mediated by ICOS signaling which acts as an integrator of glycolytic and self-renewal programming. Inhibition of ICOS at late time points leads to a reduction in TFH memory cells concomitant with decreased splenic plasma cells and circulating antibody titers. These results highlight the metabolic heterogeneity underlying distinct CD4 memory T cell subsets, linking TFH memory cell survival to sustained humoral immunity.