Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T cell development.
Details
Serval ID
serval:BIB_37BBC13C5B60
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T cell development.
Journal
Nature immunology
ISSN
1529-2916 (Electronic)
ISSN-L
1529-2908
Publication state
Published
Issued date
03/2023
Peer-reviewed
Oui
Volume
24
Number
3
Pages
501-515
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Abstract
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.
Keywords
Pyrimidines, Cell Cycle, Cell Differentiation
Pubmed
Web of science
Open Access
Yes
Create date
28/02/2023 14:53
Last modification date
16/11/2023 7:10