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- Title
Inactivation of cytidine triphosphate synthase 1 prevents fatal auto-immunity in mice.
- Authors
Soudais, Claire; Schaus, Romane; Bachelet, Camille; Minet, Norbert; Mouasni, Sara; Garcin, Cécile; Souza, Caique Lopes; David, Pierre; Cousu, Clara; Asnagli, Hélène; Parker, Andrew; Palmquist-Gomes, Paul; Sepulveda, Fernando E.; Storck, Sébastien; Meilhac, Sigolène M.; Fischer, Alain; Martin, Emmanuel; Latour, Sylvain
- Abstract
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. Cytidine nucleotide triphosphate (CTP) is a key precursor involved in the metabolism of DNA, RNA and phospholipids. In this study, the authors examine the physiological consequences of CTP synthase (Ctps) 1 and 2 deletion in vivo and demonstrate that Ctps1 protects mice from fatal autoimmunity.
- Subjects
AUTOIMMUNITY; RNA metabolism; IMMUNOLOGIC memory; TALL-1 (Protein); T cells; INTESTINAL mucosa; T cell receptors
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-45805-y