Long-lived T follicular helper cells retain plasticity and help sustain humoral immunity
| Autor: | Justin J. Taylor, Tamara C. Pereboom, Timm Maier, Christoph Hess, Ludivine C. Litzler, David Schreiner, Yusuf I. Ertuna, Nivedya Swarnalekha, Julien Roux, Carolyn G. King, Jonas Lötscher, Florian Geier, Roman P. Jakob, Marco Künzli |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Programmed cell death T cell Immunology Cell Biology 03 medical and health sciences Mice 0302 clinical medicine Immune system Immunity medicine Animals PI3K/AKT/mTOR pathway Mice Knockout Cell Death Cell Differentiation General Medicine T-Lymphocytes Helper-Inducer Acquired immune system NAD Cell biology Immunity Humoral Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Humoral immunity Receptors Purinergic P2X7 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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