Abstract
T cell-driven diseases account for considerable morbidity and disability globally and there is
an urgent need for new targeted therapies. Both cancer cells and activated T cells have an
altered redox balance, and up-regulate the DNA repair protein MTH1 that sanitizes the
oxidized nucleotide pool to avoid DNA damage and cell death. Herein we suggest that the
up-regulation of MTH1 in activated T cells correlates with their redox status, but occurs
before the ROS levels increase, challenging the established conception of MTH1 increasing as
a direct response to an increased ROS status. We also propose a heterogeneity in MTH1
levels among activated T cells, where a smaller subset of activated T cells does not upregulate
MTH1 despite activation and proliferation. The study suggests that the vast majority
of activated T cells have high MTH1 levels and are sensitive to the MTH1 inhibitor TH1579
(Karonudib) via induction of DNA damage and cell cycle arrest. TH1579 further drives the
surviving cells to the MTH1[superscript low] phenotype with altered redox status. TH1579 does not affect
resting T cells, as opposed to the established immunosuppressor Azathioprine, and no
sensitivity among other major immune cell types regarding their function can be observed.
Finally, we demonstrate a therapeutic effect in a murine model of experimental
autoimmune encephalomyelitis. In conclusion, we show proof of concept of the existence of
MTH1[superscript high] and MTH1[superscript low] activated T cells, and that MTH1 inhibition by TH1579 selectively
suppresses pro-inflammatory activated T cells. Thus, MTH1 inhibition by TH1579 may serve
as a novel treatment option against autoreactive T cells in autoimmune diseases, such as
multiple sclerosis.
