Journal Article

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

Hauck, Fabian, Schwartzentruber, Jeremy, Lenoir, Christelle, Latour, Sylvain, Palmic, Noé, Martin, Emmanuel, Fabrega, Sylvie, Nitschké, Patrick, Fischer, Alain, Jabado, Nada, Sanquer, Sylvia, Mongellaz, Cédric, Wynn, Robert F., Majewski, Jacek, Taylor, Naomi, Picard, Capucine, Esposti, Mauro Degli, Arkwright, Peter D.

2014

Overview

Loss-of-function mutations in the human CTP synthase 1 gene cause an immunodeficiency disease with impaired T cell proliferation after antigen stimulation, revealing a potential new target for immunosuppressive drugs. A novel immune deficiency A study of several unrelated families susceptible to recurrent viral diseases but in whom known primary immunodeficiencies had been excluded has led to the identification of a novel human inherited immunodeficiency, and the recognition of a molecular pathway required to mount an efficient immune response against pathogens. Loss-of-function mutations in the gene for cytidine 5′ triphosphate synthase 1 ( CTPS1 ) are associated with severe and selective impairment of T-cell proliferation after antigen stimulation, identifying the enzyme as a critical checkpoint in adaptive immunity. CTPS1 deficiency does not induce other phenotype abnormalities, so these findings suggest that CTPS1 could be a viable target for therapeutics to inhibit unwanted adaptive responses. Lymphocyte functions triggered by antigen recognition and co-stimulation signals are associated with a rapid and intense cell division, and hence with metabolism adaptation 1 . The nucleotide cytidine 5′ triphosphate (CTP) is a precursor required for the metabolism of DNA, RNA and phospholipids 2 , 3 , 4 . 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 5 , 6 , 7 . CTP synthase activity is a potentially important step for DNA synthesis in lymphocytes 8 , 9 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 45 / 45/43 / 631/250/249/2512 / 82 / 96 / 96/106 / 96/109 / 96/31 / 96/34 / 96/95 / Adaptive immunology / B-Lymphocytes - cytology / B-Lymphocytes - immunology / B-Lymphocytes - metabolism / Bacterial infections / Biochemistry, Molecular Biology / Carbon-Nitrogen Ligases - deficiency / Carbon-Nitrogen Ligases - genetics / Carbon-Nitrogen Ligases - metabolism / CD3 Complex - immunology / Cell division / Cell Proliferation / Cell research / Child, Preschool / Cytidine Triphosphate - metabolism / Deoxyribonucleic acid / DNA / Female / Genetics / Genomics / Herpes viruses / Human genetics / Humanities and Social Sciences / Humans / Immune response / Immune system / Immunodeficiency / Immunologic Deficiency Syndromes - enzymology / Immunologic Deficiency Syndromes - genetics / Immunology / Infant / Infant, Newborn / Innate immunity / Kinases / letter / Life Sciences / Lymphocyte Activation - genetics / Lymphocytes / Lymphocytes - cytology / Lymphocytes - immunology / Lymphocytes - metabolism / Male / multidisciplinary / Mutation / Mutation - genetics / Patients / Phosphorylation / Physiological aspects / Protein expression / Proteins / Pyrimidine nucleotides / Receptors, Antigen, T-Cell - immunology / Science / Streptococcus infections / T cell receptors / T-Lymphocytes - cytology / T-Lymphocytes - immunology / T-Lymphocytes - metabolism / Viral infections