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
Author(s)
Scherer S., Oberle S.G., Kanev K., Gerullis A.K., Wu M., de Almeida G.P., Puleston D.J., Baixauli F., Aly L., Greco A., Nizharadze T., Becker N.B., Hoesslin M.V., Donhauser L.V., Berner J., Chu T., McNamara H.A., Esencan Z., Roelli P., Wurmser C., Kleiter I., Vehreschild MJGT, Mayer C.A., Knolle P., Klingenspor M., Fumagalli V., Iannacone M., Prlic M., Korn T., Pearce E.L., Höfer T., Schulz A.M., Zehn D.
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
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
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