Cd28 autonomous signaling up‐regulates c‐myc expression and promotes glycolysis enabling inflammatory t cell responses in multiple sclerosis

Martina Kunk, Manolo Sambucci, Serena Ruggieri, Carola Amormino, Carla Tortorella, Claudio Gasperini, Luca Battistini, Loretta Tuosto

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Article number2926
JournalInternational Journal of Molecular Sciences
Volume20
Issue number12
DOIs
Publication statusPublished - Jun 2 2019

Keywords

  • CD28
  • Class 1A PI3K
  • C‐myc
  • Glycolysis
  • Inflammation
  • Multiple sclerosis
  • Th17 cells

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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