Impaired lymphocyte function and differentiation in CTPS1-deficient patients result from a hypomorphic homozygous mutation
Open Access
- 12 March 2020
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
Abstract
Cytidine triphosphate (CTP) synthetase 1 (CTPS1) deficiency is caused by a unique homozygous frameshift splice mutation (c.1692-1G>C, p.T566Dfs26X). CTPS1-deficient patients display severe bacterial and viral infections. CTPS1 is responsible for CTP nucleotide de novo production involved in DNA/RNA synthesis. Herein, we characterized in depth lymphocyte defects associated with CTPS1 deficiency. Immune phenotyping performed in 7 patients showed absence or low numbers of mucosal-associated T cells, invariant NKT cells, memory B cells, and NK cells, whereas other subsets were normal. Proliferation and IL-2 secretion by T cells in response to TCR activation were markedly decreased in all patients, while other T cell effector functions were preserved. The CTPS1T566Dfs26X mutant protein was found to be hypomorphic, resulting in 80%–90% reduction of protein expression and CTPS activity in cells of patients. Inactivation of CTPS1 in a T cell leukemia fully abolished cell proliferation. Expression of CTPS1T566Dfs26X failed to restore proliferation of CTPS1-deficient leukemia cells to normal, except when forcing its expression to a level comparable to that of WT CTPS1. This indicates that CTPS1T566Dfs26X retained normal CTPS activity, and thus the loss of function of CTPS1T566Dfs26X is completely attributable to protein instability. This study supports that CTPS1 represents an attractive therapeutic target to selectively inhibit pathological T cell proliferation, including lymphoma.Funding Information
- ANR (ANR-18-CE15-0025-01)
- ANR (ANR-10-IAHU-01)
- ERC (ERC-2015-PoC_Master/ERC-2015-PoC_680465_SAFEIMMUNOSUPPRESS)
- Ligue Contre le Cancer (Equipe Labellisée)
- Inserm (Dotation)
This publication has 35 references indexed in Scilit:
- Nucleoside salvage pathway kinases regulate hematopoiesis by linking nucleotide metabolism with replication stressThe Journal of Experimental Medicine, 2012
- Regulation of Human Cytidine Triphosphate Synthetase 2 by Phosphorylation*Online Journal of Public Health Informatics, 2010
- B cell subsets in healthy children: Reference values for evaluation of B cell maturation process in peripheral bloodCytometry Part B: Clinical Cytometry, 2010
- Stepwise Development of MAIT Cells in Mouse and HumanPLoS Biology, 2009
- The Biology of NKT CellsAnnual Review of Immunology, 2007
- Lymphocyte subsets in healthy children from birth through 18 years of age: The pediatric AIDS clinical trials group P1009 studyJournal of Allergy and Clinical Immunology, 2003
- Cytidine triphosphate (ctp) synthetase activity during cell cycle progression in normal and malignant t-lymphocytic cellsEuropean Journal of Cancer, 1995
- Evidence for transformation‐related increase in CTP synthetase activity in situ in human lymphoblastic leukemiaJBIC Journal of Biological Inorganic Chemistry, 1993
- Increased CTP synthetase activity in cancer cellsNature, 1978
- Characterization of EBV-genome negative “null” and “T” cell lines derived from children with acute lymphoblastic leukemia and leukemic transformed non-Hodgkin lymphomaInternational Journal of Cancer, 1977