Article Dans Une Revue Nature Communications Année : 2024

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

Pierre David
Hélène Asnagli
  • Fonction : Auteur
Andrew Parker
  • Fonction : Auteur
Sébastien Storck

Résumé

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.
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hal-04589736 , version 1 (29-05-2024)

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Claire Soudais, Romane Schaus, Camille Bachelet, Norbert Minet, Sara Mouasni, et al.. Inactivation of cytidine triphosphate synthase 1 prevents fatal auto-immunity in mice. Nature Communications, 2024, 15 (1), pp.1982. ⟨10.1038/s41467-024-45805-y⟩. ⟨hal-04589736⟩
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