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

Lymphocyte functions triggered by antigen recognition and costimulation 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 (2-4). CTP originates from two sources: a salvage pathway and a denovosynthesis 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 (5-7). CTP synthase activity is a potentially important step for DNA synthesis in lymphocytes (8,9). Here we report the identification of a loss-of-functionhomozygous mutation (rs145092287) in CTPS1 inhumans 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.
We initially studied two unrelated families (family 1 and 2) originating from the northwest region of England, whose four children suffered from severe and recurrent Epstein-Barr virus (EBV) infection, in [...]