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Open AccessArticle

CD28 Autonomous Signaling Up-Regulates C-Myc Expression and Promotes Glycolysis Enabling Inflammatory T Cell Responses in Multiple Sclerosis

1
Department of Biology and Biotechnology Charles Darwin, Sapienza University, 00185 Rome, Italy
2
Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University, 00185 Rome, Italy
3
Neuroimmunology Unit, IRCCS Santa Lucia Foundation, 00185 Rome, Italy
4
Department of Neurosciences, S. Camillo/Forlanini Hospital, 00185 Rome, Italy
*
Author to whom correspondence should be addressed.
These authors have contributed equally to this work.
Cells 2019, 8(6), 575; https://doi.org/10.3390/cells8060575
Received: 15 May 2019 / Revised: 5 June 2019 / Accepted: 7 June 2019 / Published: 11 June 2019
(This article belongs to the Special Issue The Molecular and Cellular Basis for Multiple Sclerosis)
The immunopathogenesis of multiple sclerosis (MS) depend on the expansion of specific inflammatory T cell subsets, which are key effectors of tissue damage and demyelination. Emerging studies evidence that a reprogramming of T cell metabolism may occur in MS, thus the identification of stimulatory molecules and associated signaling pathways coordinating the metabolic processes that amplify T cell inflammation in MS is pivotal. Here, we characterized the involvement of the cluster of differentiation (CD)28 and associated signaling mediators in the modulation of the metabolic programs regulating pro-inflammatory T cell functions in relapsing-remitting MS (RRMS) patients. We show that CD28 up-regulates glycolysis independent of the T cell receptor (TCR) engagement by promoting the increase of c-myc and the glucose transporter, Glut1, in RRMS CD4+ T cells. The increase of glycolysis induced by CD28 was important for the expression of inflammatory cytokines related to T helper (Th)17 cells, as demonstrated by the strong inhibition exerted by impairing the glycolytic pathway. Finally, we identified the class 1A phosphatidylinositol 3-kinase (PI3K) as the critical signaling mediator of CD28 that regulates cell metabolism and amplify specific inflammatory T cell phenotypes in MS. View Full-Text
Keywords: multiple sclerosis; inflammation; Th17 cells; glycolysis; CD28; c-myc; class 1A PI3K multiple sclerosis; inflammation; Th17 cells; glycolysis; CD28; c-myc; class 1A PI3K
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Kunkl, M.; Sambucci, M.; Ruggieri, S.; Amormino, C.; Tortorella, C.; Gasperini, C.; Battistini, L.; Tuosto, L. CD28 Autonomous Signaling Up-Regulates C-Myc Expression and Promotes Glycolysis Enabling Inflammatory T Cell Responses in Multiple Sclerosis. Cells 2019, 8, 575.

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    Doi: 10.5281/zenodo.2837004
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