NAD+ protects against EAE by regulating CD4+ T-cell differentiation

Tullius, Stefan G.; Biefer, Héctor Rodriguez Cetina; Li, Suyan; Trachtenberg, Alexander J.; Edtinger, Karoline; Quante, Markus; Krenzien, Felix; Uehara, Hirofumi; Yang, Xiaoyong; Kissick, Haydn; Kuo, Winston Patrick; Ghiran, Ionita; Fuente, Miguel A. de la; Arredouani, Mohamed S.; Camacho, Virginia; Tigges, John; Toxavidis, Vasilis; Fatimy, Rachid El; Smith, Brian D.; Vasudevan, Anju; Elkhal, Abdallah

doi:10.1038/ncomms6101

Cited by 91 publications

(139 citation statements)

References 62 publications

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“…This was dependent on glutaminolysis since DON treatment significantly reduced NAD + levels, whereas 2DG treatment increased the NAD + level in Th1/17 cells (Figure S4K). Owing to the well-characterized role of NAD + in regulating T cell proliferation, cytokine production and survival (Bruzzone et al, 2009; Tullius et al, 2014), we determined the impact of modulating NAD + on Th1/17 cell function. We observed that depletion of NAD + using FK866 (Figure S4L), an inhibitor of nicotinamide phosphoribosyltransferase ( Nampt ) that is required for the biosynthesis of NAD + (Bruzzone et al, 2009) resulted in a 2-fold decrease in the frequency of IL17 + IFNγ + population in Th1/17 cells (Figure 4C) and reduced expression of stemness-associated molecules such as Tcf7 , Bcl6 , and β-catenin (Figure 4D).…”

Section: Resultsmentioning

confidence: 99%

CD38-NAD+Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response

et al. 2018

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SUMMARY Heightened effector function and prolonged persistence, the key attributes of Th1 and Th17 cells, respectively, are key features of potent anti-tumor T cells. Here, we established ex vivo culture conditions to generate hybrid Th1/17 cells, which persisted long-term in vivo while maintaining their effector function. Using transcriptomics and metabolic profiling approaches, we showed that the enhanced anti-tumor property of Th1/17 cells was dependent on the increased NAD+-dependent activity of the histone deacetylase Sirt1. Pharmacological or genetic inhibition of Sirt1 activity impaired the anti-tumor potential of Th1/17 cells. Importantly, T cells with reduced surface expression of the NADase CD38 exhibited intrinsically higher NAD+, enhanced oxidative phosphorylation, higher glutaminolysis, and altered mitochondrial dynamics that vastly improved tumor control. Lastly, blocking CD38 expression improved tumor control even when using Th0 anti-tumor T cells. Thus, strategies targeting the CD38-NAD+ axis could increase the efficacy of anti-tumor adoptive T cell therapy.

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Section: Resultsmentioning

confidence: 99%

CD38-NAD+Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response

et al. 2018

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“…Among all the lineages of CD4+T cells, Th1 and Th17 cells are recognized as critical effector cells responsible for the development of EAE (Tullius et al . ).…”

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confidence: 97%

“…Like MS, EAE is mainly initiated by aberrant myelin antigen-specific autoreactive CD4+T-lymphocyte invasion into the CNS. Among all the lineages of CD4+T cells, Th1 and Th17 cells are recognized as critical effector cells responsible for the development of EAE (Tullius et al 2014). Th1 cell was long considered to be closely associated to mediate CNS pathology of EAE.…”

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confidence: 99%

Rifampicin attenuates experimental autoimmune encephalomyelitis by inhibiting pathogenic Th17 cells responses

Chen

et al. 2016

Journal of Neurochemistry

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Rifampicin, a broad-spectrum antibiotic, has neuroprotective, immunosuppressive, and anti-inflammatory properties. However, the effect of rifampicin on autoimmune disorders of the nervous system is not clear. In this study, we investigated whether rifampicin was beneficial to myelin oligodendrocyte glycoprotein peptide )-induced female C57BL/6 experimental autoimmune encephalomyelitis (EAE) mice, the well-established animal model of multiple sclerosis. Rifampicin treatment (daily from the first day after EAE immunization) remarkably attenuated clinical signs and loss of body weight, which are associated with suppression of inflammatory infiltration and demyelination in spinal cords of EAE mice. Furthermore, rifampicin dramatically reduced the disruption of blood-brain barrier integrity, down-regulated serum concentration of IL-6 and IL-17A, inhibited pathological Th17 cell differentiation, and modulated the expression of p-STAT3 and p-p65. These results suggest that rifampicin is effective for attenuating the clinical severity of EAE mice, which may be related to its inhibitive ability in differentiation of Th17 cell and secretion of its key effector molecule IL-17A via regulation of excessive activation of the key signaling molecules of JAK/STAT pathway. Our findings may be helpful for developing therapeutic and preventive strategies for multiple sclerosis.

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“…However, such studies would probably require a suitable animal model. At present, our work already opens a novel potential therapeutic option as treatment with nicotinamide, in addition to the supplementation of glutamine, it could be considered in future patients with an inherited GLUL defect, possibly also in secondary GS deficiency, and in patients with NAD + aberrations, as this may improve their brain functions and their immunity (Bruzzone et al 2009;Tullius et al 2014).…”

Section: Discussionmentioning

confidence: 99%

Secondary NAD⁺ deficiency in the inherited defect of glutamine synthetase

Ibrahim

Stucki

et al. 2015

J of Inher Metab Disea

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Glutamine synthetase (GS) deficiency is an ultra-rare inborn error of amino acid metabolism that has been described in only three patients so far. The disease is characterized by neonatal onset of severe encephalopathy, low levels of glutamine in blood and cerebrospinal fluid, chronic moderate hyperammonemia, and an overall poor prognosis in the absence of an effective treatment. Recently, enteral glutamine supplementation was shown to be a safe and effective therapy for this disease but there are no data available on the long-term effects of this intervention. The amino acid glutamine, severely lacking in this disorder, is central to many metabolic pathways in the human organism and is involved in the synthesis of nicotinamide adenine dinucleotide (NAD(+)) starting from tryptophan or niacin as nicotinate, but not nicotinamide. Using fibroblasts, leukocytes, and immortalized peripheral blood stem cells (PBSC) from a patient carrying a GLUL gene point mutation associated with impaired GS activity, we tested whether glutamine deficiency in this patient results in NAD(+) depletion and whether it can be rescued by supplementation with glutamine, nicotinamide or nicotinate. The present study shows that congenital GS deficiency is associated with NAD(+) depletion in fibroblasts, leukocytes and PBSC, which may contribute to the severe clinical phenotype of the disease. Furthermore, it shows that NAD(+) depletion can be rescued by nicotinamide supplementation in fibroblasts and leukocytes, which may open up potential therapeutic options for the treatment of this disorder.

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NAD+ protects against EAE by regulating CD4+ T-cell differentiation

Cited by 91 publications

References 62 publications

CD38-NAD+Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response

CD38-NAD+Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response

Rifampicin attenuates experimental autoimmune encephalomyelitis by inhibiting pathogenic Th17 cells responses

Secondary NAD⁺ deficiency in the inherited defect of glutamine synthetase

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NAD+ protects against EAE by regulating CD4+ T-cell differentiation

Cited by 91 publications

References 62 publications

CD38-NAD+Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response

CD38-NAD+Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response

Rifampicin attenuates experimental autoimmune encephalomyelitis by inhibiting pathogenic Th17 cells responses

Secondary NAD+ deficiency in the inherited defect of glutamine synthetase

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Secondary NAD⁺ deficiency in the inherited defect of glutamine synthetase