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; Höfer, Thomas; Schulz, Anna M; Zehn, Dietmar     «

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;...     »

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.      «

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...     »