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

Künzli, Marco and Schreiner, David and Pereboom, Tamara C. and Swarnalekha, Nivedya and Litzler, Ludivine C. and Lötscher, Jonas and Ertuna, Yusuf I. and Roux, Julien and Geier, Florian and Jakob, Roman P. and Maier, Timm and Hess, Christoph and Taylor, Justin J. and King, Carolyn G.. (2020) Long-lived T follicular helper cells retain plasticity and help sustain humoral immunity. Science Immunology, 5 (45). eaay5552.

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Official URL: https://edoc.unibas.ch/78829/

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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 (T; cm; ) cells, whereas the existence and functional significance of long-lived T follicular helper (T; fh; ) cells are controversial. Here, we show that T; fh; 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 T; fh; cells with high expression of hallmark T; fh; markers to at least 400 days after infection, by which time T; cm; cells are no longer found. Using single-cell RNA-seq, we demonstrate that long-lived T; fh; cells are transcriptionally distinct from T; cm; cells, maintain stemness and self-renewal gene expression, and, in contrast to T; cm; cells, are multipotent after recall. At the protein level, we show that folate receptor 4 (FR4) robustly discriminates long-lived T; fh; cells from T; cm; cells. Unexpectedly, long-lived T; fh; 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 T; fh; cell depletion concomitant with decreased splenic plasma cells and circulating antibody titers, demonstrating both unique homeostatic regulation of T; fh; 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 T; fh; cells as an attractive target for the induction of durable adaptive immunity.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Maier)
UniBasel Contributors:Maier, Timm
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Association for the Advancement of Science
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:26 Jan 2022 13:36
Deposited On:26 Jan 2022 13:36

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