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. Epub 2014 May 28.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • CD3 Complex
  • Receptors, Antigen, T-Cell
  • Cytidine Triphosphate
  • Carbon-Nitrogen Ligases
  • CTP synthetase