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

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).

Citation

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, Sylvain Latour. Inactivation of cytidine triphosphate synthase 1 prevents fatal auto-immunity in mice. Nature communications. 2024 Mar 04;15(1):1982

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PMID: 38438357

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