Research ArticleT CELLS

Long-lived T follicular helper cells retain plasticity and help sustain humoral immunity

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Science Immunology  06 Mar 2020:
Vol. 5, Issue 45, eaay5552
DOI: 10.1126/sciimmunol.aay5552

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Memory Tfh cells

Expression of a purinergic receptor P2X7R renders certain T cell subsets, including resident memory T (Trm) cells susceptible to NAD-induced cell death (NICD). Injection of an NICD protector before harvesting them improves cell recovery. Here, based on the observation that T follicular helper (Tfh) cells also express P2X7R, Künzli et al. used NICD protector to study the persistence of Tfh cells after LCMV infection in mice. They report that Tfh cells persisted for 400+ days after infection and that long-lived Tfh cells are glycolytic and are marked by high expression of folate receptor 4 (FR4). Upon reinfection, these FR4+ “memory” Tfh cells were capable of self-renewal and could also give rise to effector and central memory cells.


CD4+ memory T cells play an important role in protective immunity and are a key target in vaccine development. Many studies have focused on T central memory (Tcm) cells, whereas the existence and functional significance of long-lived T follicular helper (Tfh) cells are controversial. Here, we show that Tfh cells are highly susceptible to NAD-induced cell death (NICD) during isolation from tissues, leading to their underrepresentation in prior studies. NICD blockade reveals the persistence of abundant Tfh cells with high expression of hallmark Tfh markers to at least 400 days after infection, by which time Tcm cells are no longer found. Using single-cell RNA-seq, we demonstrate that long-lived Tfh cells are transcriptionally distinct from Tcm cells, maintain stemness and self-renewal gene expression, and, in contrast to Tcm cells, are multipotent after recall. At the protein level, we show that folate receptor 4 (FR4) robustly discriminates long-lived Tfh cells from Tcm cells. Unexpectedly, long-lived Tfh cells concurrently express a distinct glycolytic signature similar to trained immune cells, including elevated expression of mTOR-, HIF-1–, and cAMP-regulated genes. Late disruption of glycolysis/ICOS signaling leads to Tfh cell depletion concomitant with decreased splenic plasma cells and circulating antibody titers, demonstrating both unique homeostatic regulation of Tfh and their sustained function during the memory phase of the immune response. These results highlight the metabolic heterogeneity underlying distinct long-lived T cell subsets and establish Tfh cells as an attractive target for the induction of durable adaptive immunity.

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