Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T cell development.
Journal
Nature immunology
ISSN: 1529-2916
Titre abrégé: Nat Immunol
Pays: United States
ID NLM: 100941354
Informations de publication
Date de publication:
03 2023
03 2023
Historique:
received:
23
03
2022
accepted:
13
01
2023
pubmed:
17
2
2023
medline:
4
3
2023
entrez:
16
2
2023
Statut:
ppublish
Résumé
Blocking pyrimidine de novo synthesis by inhibiting dihydroorotate dehydrogenase is used to treat autoimmunity and prevent expansion of rapidly dividing cell populations including activated T cells. Here we show memory T cell precursors are resistant to pyrimidine starvation. Although the treatment effectively blocked effector T cells, the number, function and transcriptional profile of memory T cells and their precursors were unaffected. This effect occurred in a narrow time window in the early T cell expansion phase when developing effector, but not memory precursor, T cells are vulnerable to pyrimidine starvation. This vulnerability stems from a higher proliferative rate of early effector T cells as well as lower pyrimidine synthesis capacity when compared with memory precursors. This differential sensitivity is a drug-targetable checkpoint that efficiently diminishes effector T cells without affecting the memory compartment. This cell fate checkpoint might therefore lead to new methods to safely manipulate effector T cell responses.
Identifiants
pubmed: 36797499
doi: 10.1038/s41590-023-01436-x
pii: 10.1038/s41590-023-01436-x
doi:
Substances chimiques
Pyrimidines
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
501-515Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.
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