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

Science Immunology
Marco KünzliCarolyn G King

Abstract

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 cel...Continue Reading

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Citations

Jul 17, 2020·International Journal of Molecular Sciences·Elizabeth Rivas-YáñezDaniela Sauma
Mar 8, 2020·Science Immunology·Jeffrey C Nolz
Oct 21, 2020·Nature Reviews. Immunology·Mohamed A ElTanbouly, Randolph J Noelle
Aug 26, 2020·The Journal of Clinical Investigation·Fang GongPengcheng Zhou
Jan 10, 2021·Science Immunology·Nivedya SwarnalekhaCarolyn G King
Feb 16, 2021·Immunological Reviews·Brigette C Duckworth, Joanna R Groom
Apr 4, 2021·Immunology Letters·Fanny MartinezMeryem Aloulou
May 1, 2021·Cell Metabolism·Claudia C S ChiniEduardo Nunes Chini
Apr 7, 2021·Cold Spring Harbor Perspectives in Biology·Jana L RaynorHongbo Chi
Apr 30, 2021·International Immunology·Jiun-Yu JianKatsuyuki Yui
Jun 18, 2021·ImmunoTargets and Therapy·Joshua F E KoenigManel Jordana
Aug 28, 2021·Cells·Juliana Barreto de AlbuquerqueBilgi Gungor
Nov 14, 2021·Proceedings of the National Academy of Sciences of the United States of America·Kerstin NarrDaniel D Pinschewer

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