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IL-17+ CD8+ T cell suppression by dimethyl fumarate associates with clinical response in multiple sclerosis

Christina Lückel1,2, Felix Picard1, Hartmann Raifer1,3

  • 1Institute for Medical Microbiology and Hospital Hygiene, University of Marburg, 35043, Marburg, Germany.

Nature Communications
|December 18, 2019
PubMed

Insights

Dimethyl fumarate (DMF) suppresses pathogenic IL-17-producing CD8+ T cells (Tc17) in multiple sclerosis (MS) by activating the PI3K-AKT-T-BET pathway. This discovery reveals a novel immune modulation mechanism and potential therapeutic targets for MS.

Area of Science:

  • Immunology
  • Neuroimmunology
  • Pharmacology

Background:

  • Interleukin-17 (IL-17)-producing CD8+ T cells (Tc17) are implicated in multiple sclerosis (MS) pathogenesis.
  • Dimethyl fumarate (DMF) is a treatment for MS, but its mechanism of action is not fully understood.

Purpose of the Study:

  • To elucidate the mechanism by which DMF ameliorates MS by targeting Tc17 cells.
  • To identify potential therapeutic targets for MS based on DMF's action.

Main Methods:

  • Analysis of Tc17 cell frequency and gene expression in MS patients treated with DMF.
  • Investigation of the PI3K-AKT-FOXO1-T-BET pathway and its role in Tc17 regulation.
  • Studies in T-BET-deficient mice and using pathway inhibitors.

Main Results:

  • DMF treatment reduced Tc17 cell frequency and altered the RORC-to-TBX21 ratio in CD8+ T cells from MS patients.
  • DMF potentiates the PI3K-AKT-FOXO1-T-BET pathway, suppressing IL-17 and RORγt expression in a glutathione-dependent manner.
  • T-BET deficiency or inhibition of PI3K-AKT, STAT5, or reactive oxygen species blocked DMF-mediated Tc17 suppression.

Conclusions:

  • DMF exerts its therapeutic effects in MS by suppressing Tc17 cells via the AKT-T-BET pathway.
  • This study reveals a novel DMF-driven immune modulation pathway and suggests T-BET as a potential therapeutic target for MS.

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