title: CTP synthase 1 deficiency in humans reveals its central role in lymphocyte proliferation.
abstract: Lymphocyte functions triggered by antigen recognition and co-stimulation signals are associated with a rapid and intense cell division, and hence with metabolism adaptation. The nucleotide cytidine 5' triphosphate (CTP) is a precursor required for the metabolism of DNA, RNA and phospholipids. CTP originates from two sources: a salvage pathway and a de novo synthesis pathway that depends on two enzymes, the CTP synthases (or synthetases) 1 and 2 (CTPS1 with CTPS2); the respective roles of these two enzymes are not known. CTP synthase activity is a potentially important step for DNA synthesis in lymphocytes. Here we report the identification of a loss-of-function homozygous mutation (rs145092287) in CTPS1 in humans that causes a novel and life-threatening immunodeficiency, characterized by an impaired capacity of activated T and B cells to proliferate in response to antigen receptor-mediated activation. In contrast, proximal and distal T-cell receptor (TCR) signalling events and responses were only weakly affected by the absence of CTPS1. Activated CTPS1-deficient cells had decreased levels of CTP. Normal T-cell proliferation was restored in CTPS1-deficient cells by expressing wild-type CTPS1 or by addition of exogenous CTP or its nucleoside precursor, cytidine. CTPS1 expression was found to be low in resting T cells, but rapidly upregulated following TCR activation. These results highlight a key and specific role of CTPS1 in the immune system by its capacity to sustain the proliferation of activated lymphocytes during the immune response. CTPS1 may therefore represent a therapeutic target of immunosuppressive drugs that could specifically dampen lymphocyte activation.
authors.affiliation: 1] Laboratoire Activation Lymphocytaire et Susceptibilité à l'EBV, INSERM UMR 1163, Hôpital Necker Enfants-Malades, Paris 75015, France [2] Université Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris 75015, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Martin
authors.affiliation: 1] Laboratoire Activation Lymphocytaire et Susceptibilité à l'EBV, INSERM UMR 1163, Hôpital Necker Enfants-Malades, Paris 75015, France [2] Université Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris 75015, France.
authors.forename: Noé
authors.initials: N
authors.lastname: Palmic
authors.affiliation: Laboratoire de Biochimie Métabolomique et Protéomique, Hôpital Necker Enfants-Malades, Paris 75015, France.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Sanquer
authors.affiliation: 1] Laboratoire Activation Lymphocytaire et Susceptibilité à l'EBV, INSERM UMR 1163, Hôpital Necker Enfants-Malades, Paris 75015, France [2] Université Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris 75015, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Lenoir
authors.affiliation: 1] Laboratoire Activation Lymphocytaire et Susceptibilité à l'EBV, INSERM UMR 1163, Hôpital Necker Enfants-Malades, Paris 75015, France [2] Université Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris 75015, France.
authors.forename: Fabian
authors.initials: F
authors.lastname: Hauck
authors.affiliation: Hematopoiesis and Immunotherapy, CNRS-UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier 34293, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Mongellaz
authors.affiliation: 1] Université Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris 75015, France [2] Plateforme Vecteurs Viraux et Transfert de Gènes, IFR94, Hôpital Necker Enfants-Malades, Paris 75015, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Fabrega
authors.affiliation: 1] Université Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris 75015, France [2] Service de Bioinformatique, Hôpital Necker Enfants-Malades, Paris 75015, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschké
authors.affiliation: 1] University of Manchester, Royal Manchester Children's Hospital, Manchester M13 0WL, UK [2] Italian Institute of Technology, Genoa 16163, Italy.
authors.forename: Mauro Degli
authors.initials: MD
authors.lastname: Esposti
authors.affiliation: McGill University and Genome Québec Innovation Centre, Montréal H3A 0G1, Canada.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schwartzentruber
authors.affiliation: Hematopoiesis and Immunotherapy, CNRS-UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier 34293, France.
authors.forename: Naomi
authors.initials: N
authors.lastname: Taylor
authors.affiliation: McGill University and Genome Québec Innovation Centre, Montréal H3A 0G1, Canada.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.affiliation: 1] McGill University and Genome Québec Innovation Centre, Montréal H3A 0G1, Canada [2] Department of Pediatrics, McGill University Health Center Research Institute, Montréal H3H 1P3, Canada.
authors.forename: Nada
authors.initials: N
authors.lastname: Jabado
authors.affiliation: University of Manchester, Royal Manchester Children's Hospital, Manchester M13 0WL, UK.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Wynn
authors.affiliation: 1] Université Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris 75015, France [2] Centre d'Etude des Déficits Immunitaires, Hôpital Necker Enfants-Malades, AP-HP, Paris 75015, France [3] Laboratoire Génétique Humaine des Maladies Infectieuses, INSERM UMR 1163, Hôpital Necker Enfants-Malades, Paris 75015, France.
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.affiliation: 1] Laboratoire Activation Lymphocytaire et Susceptibilité à l'EBV, INSERM UMR 1163, Hôpital Necker Enfants-Malades, Paris 75015, France [2] Université Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris 75015, France [3] Unité d'Immunologie et Hématologie Pédiatrique, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Paris 75015, France [4] Collège de France, Paris 75005, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.affiliation: 1] University of Manchester, Royal Manchester Children's Hospital, Manchester M13 0WL, UK [2].
authors.forename: Peter D
authors.initials: PD
authors.lastname: Arkwright
authors.affiliation: 1] Laboratoire Activation Lymphocytaire et Susceptibilité à l'EBV, INSERM UMR 1163, Hôpital Necker Enfants-Malades, Paris 75015, France [2] Université Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris 75015, France [3] Laboratoire de Biochimie Métabolomique et Protéomique, Hôpital Necker Enfants-Malades, Paris 75015, France [4].
authors.forename: Sylvain
authors.initials: S
authors.lastname: Latour
mesh_terms: D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology; D019731:Carbon-Nitrogen Ligases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002675:Child, Preschool; D003570:Cytidine Triphosphate / Q000378:metabolism; D005260:Female; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000201:enzymology / Q000235:genetics; D007223:Infant; D007231:Infant, Newborn; D008213:Lymphocyte Activation / Q000235:genetics; D008214:Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D008297:Male; D009154:Mutation / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D017252:CD3 Complex; D011948:Receptors, Antigen, T-Cell; D003570:Cytidine Triphosphate; D019731:Carbon-Nitrogen Ligases; C019951:CTP synthetase