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

Autor: Soudais C; Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, Inserm UMR 1163, Institut Imagine, Paris, France. claire.soudais@inserm.fr.; Université de Paris Cité, Paris, France. claire.soudais@inserm.fr., Schaus R; Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, Inserm UMR 1163, Institut Imagine, Paris, France., Bachelet C; Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, Inserm UMR 1163, Institut Imagine, Paris, France.; Université de Paris Cité, Paris, France., Minet N; Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, Inserm UMR 1163, Institut Imagine, Paris, France.; Université de Paris Cité, Paris, France., Mouasni S; Laboratory of Molecular Basis of Altered Immune Homeostasis Inserm UMR 1163, Institut Imagine, Paris, France., Garcin C; Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, Inserm UMR 1163, Institut Imagine, Paris, France.; Université de Paris Cité, Paris, France., Souza CL; Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, Inserm UMR 1163, Institut Imagine, Paris, France.; Université de Paris Cité, Paris, France., David P; Transgenesis Platform, Laboratoire d'Expérimentation Animale et Transgenèse (LEAT), Institut Imagine-Structure Fédérative de Recherche Necker INSERM US24/CNRS, UMS3633, Paris, France., Cousu C; Université Paris Cité, CNRS UMR 8253, INSERM U1151, Institut Necker Enfants Malades, F-75015, Paris, France., Asnagli H; Step-Pharma, Technoparc du Pays-de-Gex, Saint-Genis-Pouilly, France., Parker A; Step-Pharma, Technoparc du Pays-de-Gex, Saint-Genis-Pouilly, France., Palmquist-Gomes P; Université de Paris Cité, Paris, France.; Imagine - Institut Pasteur, Unit of Heart Morphogenesis, INSERM UMR1163, F-75015, Paris, France., Sepulveda FE; Laboratory of Molecular Basis of Altered Immune Homeostasis Inserm UMR 1163, Institut Imagine, Paris, France., Storck S; Université Paris Cité, CNRS UMR 8253, INSERM U1151, Institut Necker Enfants Malades, F-75015, Paris, France., Meilhac SM; Université de Paris Cité, Paris, France.; Imagine - Institut Pasteur, Unit of Heart Morphogenesis, INSERM UMR1163, F-75015, Paris, France., Fischer A; Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, Inserm UMR 1163, Institut Imagine, Paris, France.; Collège de France, Paris, France., Martin E; Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, Inserm UMR 1163, Institut Imagine, Paris, France., Latour S; Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, Inserm UMR 1163, Institut Imagine, Paris, France. sylvain.latour@inserm.fr.; Université de Paris Cité, Paris, France. sylvain.latour@inserm.fr.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Mar 04; Vol. 15 (1), pp. 1982. Date of Electronic Publication: 2024 Mar 04.
DOI: 10.1038/s41467-024-45805-y
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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