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

CTPS1 inhibition in fully MHC-mismatched and haploidentical hematopoietic stem cell transplantation models completely blocks aGVHD induction, linked to significantly reduced alloreactive effector T cell expansion.

• Why it matters: aGVHD and skin graft rejection after allogeneic transplantation are driven by alloreactive T cells, and CTPS1-mediated de novo CTP synthesis is a key requirement for activated T cell proliferation.
• What they did: The study used Ctps1-deficient T cells in MHC-mismatched and haploidentical transplantation models and in skin graft rejection models, and also tested a specific CTPS1 inhibitor to treat mice with lethal aGVHD.
• The result: CTPS1 loss prevents aGVHD induction and reduces effector expansion; in skin grafts it delays destruction but does not prevent rejection, and later T cell–mediated rejection proceeds independently of CTPS1, while inhibitor treatment rescues mice from lethal aGVHD.

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