Inhibition of the CTP synthase 1 prevents GVHD and delays skin graft rejection revealing distinct alloreactive T cell responses.

Acute graft-versus-host disease (aGVHD), following allogeneic hematopoietic stem cell transplantation, and organ rejection are serious immune-mediated complications driven by alloreactive T cells. CTPS1, a crucial enzyme for de novo CTP synthesis, is essential for the proliferation of activated T cells, representing an attractive therapeutic target for controlling T cell-mediated pathologies. In this study, using Ctps1-deficient T cells in fully MHC-mismatched and haploidentical hematopoietic stem cell transplantation models, a complete blockage in the induction of aGVHD is observed in association with significantly reduced alloreactive effector T cell expansion. In skin graft rejection models, expansion of alloreactive Ctps1-deficient T cells is reduced, and graft destruction is delayed but not prevented. Notably, the healing process allows T cells to mediate skin graft rejection independently of CTPS1. Finally, treatment with a specific CTPS1 inhibitor rescues mice from lethal aGVHD. Our results underscore the pivotal role of CTPS1 in driving alloreactive T cell responses, highlighting its potential for aGVHD treatment.