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

Claire Soudais (), Romane Schaus, Camille Bachelet, Norbert Minet, Sara Mouasni, Cécile Garcin, Caique Lopes Souza, Pierre David, Clara Cousu, Hélène Asnagli, Andrew Parker, Paul Palmquist-Gomes, Fernando E. Sepulveda, Sébastien Storck, Sigolène M. Meilhac, Alain Fischer, Emmanuel Martin and Sylvain Latour ()
Additional contact information
Claire Soudais: Inserm UMR 1163, Institut Imagine
Romane Schaus: Inserm UMR 1163, Institut Imagine
Camille Bachelet: Inserm UMR 1163, Institut Imagine
Norbert Minet: Inserm UMR 1163, Institut Imagine
Sara Mouasni: Laboratory of Molecular Basis of Altered Immune Homeostasis Inserm UMR 1163, Institut Imagine
Cécile Garcin: Inserm UMR 1163, Institut Imagine
Caique Lopes Souza: Inserm UMR 1163, Institut Imagine
Pierre David: Institut Imagine-Structure Fédérative de Recherche Necker INSERM US24/CNRS
Clara Cousu: Université Paris Cité, CNRS UMR 8253, INSERM U1151, Institut Necker Enfants Malades
Hélène Asnagli: Technoparc du Pays-de-Gex
Andrew Parker: Technoparc du Pays-de-Gex
Paul Palmquist-Gomes: Université de Paris Cité
Fernando E. Sepulveda: Laboratory of Molecular Basis of Altered Immune Homeostasis Inserm UMR 1163, Institut Imagine
Sébastien Storck: Université Paris Cité, CNRS UMR 8253, INSERM U1151, Institut Necker Enfants Malades
Sigolène M. Meilhac: Université de Paris Cité
Alain Fischer: Inserm UMR 1163, Institut Imagine
Emmanuel Martin: Inserm UMR 1163, Institut Imagine
Sylvain Latour: Inserm UMR 1163, Institut Imagine

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45805-y

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