Publication Date:
2014-05-30
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Martin, Emmanuel -- Palmic, Noe -- Sanquer, Sylvia -- Lenoir, Christelle -- Hauck, Fabian -- Mongellaz, Cedric -- Fabrega, Sylvie -- Nitschke, Patrick -- Esposti, Mauro Degli -- Schwartzentruber, Jeremy -- Taylor, Naomi -- Majewski, Jacek -- Jabado, Nada -- Wynn, Robert F -- Picard, Capucine -- Fischer, Alain -- Arkwright, Peter D -- Latour, Sylvain -- G1001799/Medical Research Council/United Kingdom -- WT095219MA/Wellcome Trust/United Kingdom -- England -- Nature. 2014 Jun 12;510(7504):288-92. doi: 10.1038/nature13386. Epub 2014 May 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Laboratoire Activation Lymphocytaire et Susceptibilite a l'EBV, INSERM UMR 1163, Hopital Necker Enfants-Malades, Paris 75015, France [2] Universite Paris Descartes Sorbonne Paris Cite, Institut Imagine, Paris 75015, France. ; Laboratoire de Biochimie Metabolomique et Proteomique, Hopital Necker Enfants-Malades, Paris 75015, France. ; Hematopoiesis and Immunotherapy, CNRS-UMR 5535, Institut de Genetique Moleculaire de Montpellier, Montpellier 34293, France. ; 1] Universite Paris Descartes Sorbonne Paris Cite, Institut Imagine, Paris 75015, France [2] Plateforme Vecteurs Viraux et Transfert de Genes, IFR94, Hopital Necker Enfants-Malades, Paris 75015, France. ; 1] Universite Paris Descartes Sorbonne Paris Cite, Institut Imagine, Paris 75015, France [2] Service de Bioinformatique, Hopital Necker Enfants-Malades, Paris 75015, France. ; 1] University of Manchester, Royal Manchester Children's Hospital, Manchester M13 0WL, UK [2] Italian Institute of Technology, Genoa 16163, Italy. ; McGill University and Genome Quebec Innovation Centre, Montreal H3A 0G1, Canada. ; 1] McGill University and Genome Quebec Innovation Centre, Montreal H3A 0G1, Canada [2] Department of Pediatrics, McGill University Health Center Research Institute, Montreal H3H 1P3, Canada. ; University of Manchester, Royal Manchester Children's Hospital, Manchester M13 0WL, UK. ; 1] Universite Paris Descartes Sorbonne Paris Cite, Institut Imagine, Paris 75015, France [2] Centre d'Etude des Deficits Immunitaires, Hopital Necker Enfants-Malades, AP-HP, Paris 75015, France [3] Laboratoire Genetique Humaine des Maladies Infectieuses, INSERM UMR 1163, Hopital Necker Enfants-Malades, Paris 75015, France. ; 1] Laboratoire Activation Lymphocytaire et Susceptibilite a l'EBV, INSERM UMR 1163, Hopital Necker Enfants-Malades, Paris 75015, France [2] Universite Paris Descartes Sorbonne Paris Cite, Institut Imagine, Paris 75015, France [3] Unite d'Immunologie et Hematologie Pediatrique, Assistance Publique-Hopitaux de Paris (AP-HP), Hopital Necker Enfants-Malades, Paris 75015, France [4] College de France, Paris 75005, France. ; 1] University of Manchester, Royal Manchester Children's Hospital, Manchester M13 0WL, UK [2]. ; 1] Laboratoire Activation Lymphocytaire et Susceptibilite a l'EBV, INSERM UMR 1163, Hopital Necker Enfants-Malades, Paris 75015, France [2] Universite Paris Descartes Sorbonne Paris Cite, Institut Imagine, Paris 75015, France [3] Laboratoire de Biochimie Metabolomique et Proteomique, Hopital Necker Enfants-Malades, Paris 75015, France [4].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24870241" target="_blank"〉PubMed〈/a〉
Keywords:
Antigens, CD3/immunology
;
B-Lymphocytes/cytology/immunology/metabolism
;
Carbon-Nitrogen Ligases/*deficiency/genetics/*metabolism
;
Cell Proliferation
;
Child, Preschool
;
Cytidine Triphosphate/metabolism
;
Female
;
Humans
;
Immunologic Deficiency Syndromes/enzymology/genetics
;
Infant
;
Infant, Newborn
;
*Lymphocyte Activation/genetics
;
Lymphocytes/*cytology/immunology/metabolism
;
Male
;
Mutation/genetics
;
Receptors, Antigen, T-Cell/immunology
;
T-Lymphocytes/cytology/immunology/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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