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

Nat Immunol. 2023 Mar;24(3):501-515. doi: 10.1038/s41590-023-01436-x. Epub 2023 Feb 16. PMID: 36797499.

Authors/Editors: Scherer S, Oberle SG, Kanev K, Gerullis AK, Wu M, de Almeida GP, Puleston DJ, Baixauli F, Aly L, Greco A, Nizharadze T, Becker NB, Hoesslin MV, Donhauser LV, Berner J, Chu T, McNamara HA, Esencan Z, Roelli P, Wurmser C, Kleiter I, Vehreschild MJGT, Mayer CA, Knolle P, Klingenspor M, Fumagalli V, Iannacone M, Prlic M, Korn T, Pearce EL, Höfer T, Schulz AM, Zehn D.
Publication Date: 2023



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.


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