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

Martin, E.; Palmic, N.; Sanquer, S.; Lenoir, C.; Hauck, F.; Mongellaz, C.; Fabrega, S.; Nitschke, P.; Esposti, M. D.; Schwartzentruber, J.; Taylor, N.; Majewski, J.; Jabado, N.; Wynn, R. F.; Picard, C.; Fischer, A.; Arkwright, P. D.; Latour, S.


2014-06-12 / vol 510 / pages 288-92


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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10.1038/nature13386 nature13386 [pii]

1476-4687 (Electronic) 0028-0836 (Linking)


Female; Humans; Cell Proliferation; Male; *Lymphocyte Activation/genetics; Antigens, CD3/immunology; B-Lymphocytes/cytology/immunology/metabolism; Carbon-Nitrogen Ligases/*deficiency/genetics/*metabolism; Child, Preschool; Cytidine Triphosphate/metabolism; Immunologic Deficiency Syndromes/enzymology/genetics; Infant; Infant, Newborn; Lymphocytes/*cytology/immunology/metabolism; Mutation/genetics; Receptors, Antigen, T-Cell/immunology; T-Lymphocytes/cytology/immunology/metabolism

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