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

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.

Secondary infections rejuvenate the intestinal CD103+ tissue-resident memory T cell pool.

Resident T lymphocytes (TRM) protect tissues during pathogen reexposure. Although TRM phenotype and restricted migratory pattern are established, we have a limited understanding of their response kinetics, stability, and turnover during reinfections. Such characterizations have been restricted by the absence of in vivo fate-mapping systems. We generated two mouse models, one to stably mark CD103+ T cells (a marker of TRM cells) and the other to specifically deplete CD103- T cells. Using these models, we observed that intestinal CD103+ T cells became activated during viral or bacterial reinfection, remained organ-confined, and retained their original phenotype but failed to reexpand. Instead, the population was largely rejuvenated by CD103+ T cells formed de novo during reinfections. This pattern remained unchanged upon deletion of antigen-specific circulating T cells, indicating that the lack of expansion was not due to competition with circulating subsets. Thus, although intestinal CD103+ resident T cells survived long term without antigen, they lacked the ability of classical memory T cells to reexpand. This indicated that CD103+ T cell populations could not autonomously maintain themselves. Instead, their numbers were sustained during reinfection via de novo formation from CD103- precursors. Moreover, in contrast to CD103- cells, which require antigen plus inflammation for their activation, CD103+ TRM became fully activated follwing exposure to inflammation alone. Together, our data indicate that primary CD103+ resident memory T cells lack secondary expansion potential and require CD103- precursors for their long-term maintenance.