Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T cell development

Scherer, Stefanie; Oberle, Susanne G.; Kanev, Kristiyan; Gerullis, Ann-Katrin; Wu, Ming; de Almeida, Gustavo P.; Puleston, Daniel J.; Baixauli, Francesc; Aly, Lilian; Greco, Alessandro; Nizharadze, Tamar; Becker, Nils B.; Hoesslin, Madlaina V.; Donhauser, Lara V.; Berner, Jacqueline; Chu, Talyn; McNamara, Hayley A.; Esencan, Zeynep; Roelli, Patrick; Wurmser, Christine; Kleiter, Ingo; Vehreschild, Maria J. G. T.; Mayer, Christoph A.; Knolle, Percy; Klingenspor, Martin; Fumagalli, Valeria; Iannacone, Matteo; Prlic, Martin; Korn, Thomas; Pearce, Erika L.; Hoefer, Thomas; Schulz, Anna M. und Zehn, Dietmar (2023): Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T cell development. In: Nature Immunology, Bd. 24, Nr. 3: 501-+

Abstract

Here the authors show that dihydroorotate dehydrogenase in the de novo pyrimidine synthesis pathway functions as a cell fate checkpoint that can be targeted to specifically diminish the number and function of effector T cells without affecting the memory T cell pool and response to infection. 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198