CTP synthase 1 deficiency in humans reveals its central role in lymphocyte proliferation

Nature. 2014 Jun 12;510(7504):288-92. doi: 10.1038/nature13386.

Emmanuel Martin ¹, Noé Palmic ¹, Sylvia Sanquer ², Christelle Lenoir ¹, Fabian Hauck ¹, Cédric Mongellaz ³, Sylvie Fabrega ⁴, Patrick Nitschké ⁵, Mauro Degli Esposti ⁶, Jeremy Schwartzentruber ⁷, Naomi Taylor ³, Jacek Majewski ⁷, Nada Jabado ⁸, Robert F Wynn ⁹, Capucine Picard ¹⁰, Alain Fischer ¹¹, Peter D Arkwright ¹², Sylvain Latour ¹³

Affiliations

1 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.
2 Laboratoire de Biochimie Métabolomique et Protéomique, Hôpital Necker Enfants-Malades, Paris 75015, France.
3 Hematopoiesis and Immunotherapy, CNRS-UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier 34293, France.
4 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.
5 1] Université Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris 75015, France [2] Service de Bioinformatique, Hôpital Necker Enfants-Malades, Paris 75015, France.
6 1] University of Manchester, Royal Manchester Children's Hospital, Manchester M13 0WL, UK [2] Italian Institute of Technology, Genoa 16163, Italy.
7 McGill University and Genome Québec Innovation Centre, Montréal H3A 0G1, Canada.
8 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.
9 University of Manchester, Royal Manchester Children's Hospital, Manchester M13 0WL, UK.
10 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.
11 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.
12 1] University of Manchester, Royal Manchester Children's Hospital, Manchester M13 0WL, UK [2].
13 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].

PMID: 24870241 DOI: 10.1038/nature13386

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.

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