5-Fluorouracil targets thymidylate synthase in the selective suppression of T(H)17 cell differentiation

While it is well established that treatment of cancer patients with 5-Fluorouracil (5-FU) can result in immune suppression, the exact function of 5-FU in the modulation of immune cells has not been fully established. We found that low dose 5-FU selectively suppresses T(H)17 and T(H)1 cell differentiation without apparent effect on Treg, T(H)2, and significantly suppresses thymidylate synthase (TS) expression in T(H)17 and T(H)1 cells but has a lesser effect in tumor cells and macrophages. Interestingly, the basal expression of TS varies significantly between T helper phenotypes and knockdown of TS significantly impairs T(H)17 and T(H)1 cell differentiation without affecting the differentiation of either Treg or T(H)2 cells. Finally, low dose 5-FU is effective in ameliorating colitis development by suppressing T(H)17 and T(H)1 cell development in a T cell transfer colitis model. Taken together, the results highlight the importance of the anti-inflammatory functions of low dose 5-FU by selectively suppressing T(H)17 and T(H)1 immune responses.