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Inactivation of cytidine triphosphate synthase 1 prevents fatal auto-immunity in mice.

Claire SoudaisRomane SchausCamille BacheletNorbert MinetSara MouasniCécile GarcinCaique Lopes SouzaPierre DavidClara CousuHélène AsnagliAndrew ParkerPaul Palmquist-GomesFernando E SepulvedaSébastien StorckSigolène M MeilhacAlain FischerEmmanuel MartinSylvain Latour
Published in: Nature communications (2024)
De novo synthesis of the pyrimidine, cytidine triphosphate (CTP), is crucial for DNA/RNA metabolism and depends on the CTP synthetases, CTPS1 and -2. Partial CTPS1 deficiency in humans has previously been shown to lead to immunodeficiency, with impaired expansion of T and B cells. Here, we examine the effects of conditional and inducible inactivation of Ctps1 and/or Ctps2 on mouse embryonic development and immunity. We report that deletion of Ctps1, but not Ctps2, is embryonic-lethal. Tissue and cells with high proliferation and renewal rates, such as intestinal epithelium, erythroid and thymic lineages, activated B and T lymphocytes, and memory T cells strongly rely on CTPS1 for their maintenance and growth. However, both CTPS1 and CTPS2 are required for T cell proliferation following TCR stimulation. Deletion of Ctps1 in T cells or treatment with a CTPS1 inhibitor rescued Foxp3-deficient mice from fatal systemic autoimmunity and reduced the severity of experimental autoimmune encephalomyelitis. These findings support that CTPS1 may represent a target for immune suppression.
Keyphrases
  • cell proliferation
  • type diabetes
  • regulatory t cells
  • signaling pathway
  • mouse model
  • cell cycle
  • cell cycle arrest
  • cell free
  • nucleic acid