Impaired lymphocyte function and differentiation in CTPS1-deficient patients result from a hypomorphic homozygous mutation

Martin, Emmanuel; Minet, Norbert; Boschat, Anne-Claire; Sanquer, Sylvia; Sobrino, Steicy; Lenoir, Christelle; Villartay, Jean‐Pierre de; Leites-de-Moraes, Maria; Pïcard, Capucine; Soudais, Claire; Bourne, Tim; Hambleton, Sophie; Hughes, Stephen; Wynn, Robert; Briggs, Tracy A; Patel, Smita Y.; Lawrence, Monica G.; Fischer, Alain; Arkwright, Peter D.; Latour, Sylvain

doi:10.1172/jci.insight.133880

Cited by 36 publications

(70 citation statements)

References 33 publications

(51 reference statements)

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“…It has been shown that CTPS1 is decisively involved in promoting the proliferation of T cells following their activation. T cells from patients displaying a CTPS1‐deficiency have been shown to lack the capacity to sustain proliferative responses and adequate IL‐2 production in response to TCR activation (Martin et al, 2014, 2020). To delineate, if DON exerts the observed age‐specific immunosuppressive effects through inhibiting CTPS1, we made use of an alternative way to block the glutaminolysis pathway by using CB‐839, a specific inhibitor of the phosphate‐activated mitochondrial glutaminase (GLS1) (Gross et al, 2014).…”

Section: Resultsmentioning

confidence: 99%

Targeting age‐specific changes in CD4⁺ T cell metabolism ameliorates alloimmune responses and prolongs graft survival

et al. 2021

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Age impacts alloimmunity. Effects of aging on T‐cell metabolism and the potential to interfere with immunosuppressants have not been explored yet. Here, we dissected metabolic pathways of CD4+ and CD8+ T cells in aging and offer novel immunosuppressive targets. Upon activation, CD4+ T cells from old mice failed to exhibit adequate metabolic reprogramming resulting into compromised metabolic pathways, including oxidative phosphorylation (OXPHOS) and glycolysis. Comparable results were also observed in elderly human patients. Although glutaminolysis remained the dominant and age‐independent source of mitochondria for activated CD4+ T cells, old but not young CD4+ T cells relied heavily on glutaminolysis. Treating young and old murine and human CD4+ T cells with 6‐diazo‐5‐oxo‐l‐norleucine (DON), a glutaminolysis inhibitor resulted in significantly reduced IFN‐γ production and compromised proliferative capacities specifically of old CD4+ T cells. Of translational relevance, old and young mice that had been transplanted with fully mismatched skin grafts and treated with DON demonstrated dampened Th1‐ and Th17‐driven alloimmune responses. Moreover, DON diminished cytokine production and proliferation of old CD4+ T cells in vivo leading to a significantly prolonged allograft survival specifically in old recipients. Graft prolongation in young animals, in contrast, was only achieved when DON was applied in combination with an inhibition of glycolysis (2‐deoxy‐d‐glucose, 2‐DG) and OXPHOS (metformin), two alternative metabolic pathways. Notably, metabolic treatment had not been linked to toxicities. Remarkably, immunosuppressive capacities of DON were specific to CD4+ T cells as adoptively transferred young CD4+ T cells prevented immunosuppressive capacities of DON on allograft survival in old recipients. Depletion of CD8+ T cells did not alter transplant outcomes in either young or old recipients. Taken together, our data introduce an age‐specific metabolic reprogramming of CD4+ T cells. Targeting those pathways offers novel and age‐specific approaches for immunosuppression.

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Section: Resultsmentioning

confidence: 99%

Targeting age‐specific changes in CD4⁺ T cell metabolism ameliorates alloimmune responses and prolongs graft survival

et al. 2021

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“…All patients described thus far with CTPS1 deficiency harbor a homozygous missense G-> C mutation at base 1692 of the CTPS1 gene (rs145092287) that alters an intronic splice acceptor site. While the mutation does not alter CTPS1 catalytic activity, it causes 80-90% loss of CTPS1 protein abundance (16). The high prevalence of B-cell driven EBV-associated diseases in people with CTPS1 deficiency raises the question of how EBV-driven lymphomas arise at high frequency, despite pronounced defects in lymphocyte metabolism.…”

Section: Introductionmentioning

confidence: 99%

“…The high prevalence of B-cell driven EBV-associated diseases in people with CTPS1 deficiency raises the question of how EBV-driven lymphomas arise at high frequency, despite pronounced defects in lymphocyte metabolism. Patients with CTPS1 deficiency have normal total T and B-cell numbers, though reduced frequency of memory B-cells, the site of long-term EBV persistence (16). Whether CTPS2 may have more important roles in EBV-infected B-cells than in T and NK cells, and how CTPS1 deficiency alters the latent versus lytic stages of the EBV lifecycle remain unknown.…”

Section: Introductionmentioning

confidence: 99%

“…Whether CTPS2 may have more important roles in EBV-infected B-cells than in T and NK cells, and how CTPS1 deficiency alters the latent versus lytic stages of the EBV lifecycle remain unknown. B-cells from individuals with CTPS1 deficiency exhibit defects in proliferation (16,23).…”

Section: Introductionmentioning

confidence: 99%

“…Autosomal recessive mutations of the cytidine 5’ triphosphate synthetase 1 CTPS1 gene cause a primary immunodeficiency syndrome characterized by impaired T-cell proliferation, low numbers of invariant and mucosal-associated T-cells and NK cells, and susceptibility to encapsulated bacterial and chronic viral infections, particularly by EBV and the related varicella zoster virus (15, 16). Most CTPS1 deficient patients experienced EBV disease, including severe infectious mononucleosis, chronic EBV viremia and EBV-associated primary CNS lymphomas (16). Extra-hematopoietic manifestations of CTPS1 deficiency have not been reported, and hematopoietic stem cell transplantation is curative (17).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Epstein-Barr Virus Induced Cytidine Metabolism Roles in Transformed B-cell Growth and Survival

Liang

Wang

Yiu

et al. 2021

Preprint

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Epstein-Barr virus (EBV) is associated with 200,000 cancers annually, including B-cell lymphomas in immunosuppressed hosts. Hypomorphic mutations of the de novo pyrimidine synthesis pathway enzyme cytidine 5’ triphosphate synthase 1 (CTPS1) suppress cell mediated immunity, resulting in fulminant EBV infection and EBV+ central nervous system (CNS) lymphomas. Since CTP is a critical precursor for DNA, RNA and phospholipid synthesis, this observation raises the question of whether the isozyme CTPS2 or cytidine salvage pathways help meet CTP demand in EBV-infected B-cells. Here, we found that EBV upregulated CTPS1 and CTPS2 with distinct kinetics in newly infected B-cells. While CRISPR CTPS1 knockout caused DNA damage and proliferation defects in lymphoblastoid cell lines (LCL), which express the EBV latency III program observed in CNS lymphomas, double CTPS1/2 knockout caused stronger phenotypes. EBNA2, MYC and non-canonical NF-□B positively regulated CTPS1 expression. CTPS1 depletion impaired EBV lytic DNA synthesis, suggesting that latent EBV may drive pathogenesis with CTPS1 deficiency. Cytidine rescued CTPS1/2 deficiency phenotypes in EBV-transformed LCL and Burkitt B-cells, highlighting CTPS1/2 as a potential therapeutic target for EBV-driven lymphoproliferative disorders. Collectively, our results suggest that CTPS1 and CTPS2 have partially redundant roles in EBV-transformed B-cells and provide insights into EBV pathogenesis with CTPS1 deficiency.

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Immunodeficiency, Leukemia, and Lymphoma

Srinivasan

Sinha²,

Frazer³

2022

Interdisciplinary Cancer Research

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Impaired lymphocyte function and differentiation in CTPS1-deficient patients result from a hypomorphic homozygous mutation

Cited by 36 publications

References 33 publications

Targeting age‐specific changes in CD4⁺ T cell metabolism ameliorates alloimmune responses and prolongs graft survival

Targeting age‐specific changes in CD4⁺ T cell metabolism ameliorates alloimmune responses and prolongs graft survival

Epstein-Barr Virus Induced Cytidine Metabolism Roles in Transformed B-cell Growth and Survival

Immunodeficiency, Leukemia, and Lymphoma

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Impaired lymphocyte function and differentiation in CTPS1-deficient patients result from a hypomorphic homozygous mutation

Cited by 36 publications

References 33 publications

Targeting age‐specific changes in CD4+ T cell metabolism ameliorates alloimmune responses and prolongs graft survival

Targeting age‐specific changes in CD4+ T cell metabolism ameliorates alloimmune responses and prolongs graft survival

Epstein-Barr Virus Induced Cytidine Metabolism Roles in Transformed B-cell Growth and Survival

Immunodeficiency, Leukemia, and Lymphoma

Contact Info

Product

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Targeting age‐specific changes in CD4⁺ T cell metabolism ameliorates alloimmune responses and prolongs graft survival

Targeting age‐specific changes in CD4⁺ T cell metabolism ameliorates alloimmune responses and prolongs graft survival