Preferential recruitment of interferon-gamma-expressing TH17 cells in multiple sclerosis

Ann Neurol. 2009 Sep;66(3):390-402. doi: 10.1002/ana.21748.


Objective: There is substantial evidence supporting the role of interferon (IFN)-gamma-producing T helper (T(H)) 1 and interleukin (IL)-17-expressing T(H)17 lymphocytes in multiple sclerosis (MS) and its animal model, experimental allergic encephalomyelitis (EAE). However, to date little is known about the potential cooperative interplay between these 2 cytokines. In the current study, we sought to evaluate the frequency of IFN-gamma-expressing T(H)17 lymphocytes in MS and EAE, and study their recruitment into the central nervous system (CNS).

Methods: Human T(H)17 lymphocytes were expanded in vitro from the blood of healthy controls and relapsing MS patients using IL-23. Immune cell migration to the CNS was assessed in vitro with primary cultures of human blood-brain barrier (BBB)-derived endothelial cells, and in vivo in EAE mice.

Results: We demonstrate that in response to IL-23, human memory lymphocytes expand into a T(H)17 phenotype, with a subpopulation of cells simultaneously expressing IFN-gamma and IL-17. We note that lymphocytes obtained from the blood of relapsing MS patients have an increased propensity to expand into IFN-gamma-producing T(H)17 cells and identify numerous T lymphocytes coexpressing IL-17 and IFN-gamma in brain tissue of MS patients. We also find lymphocytes expressing both the T(H)1- and the T(H)17-associated transcription factors ROR gamma t and T-bet, in situ and in vitro. We further provide in vitro and in vivo evidence that IFN-gamma(+) T(H)17 lymphocytes preferentially cross the human BBB and accumulate in the CNS of mice during the effector phase of EAE.

Interpretation: Our data underscore the involvement of IFN-gamma(+) T(H)17 lymphocytes in the pathology of MS and EAE and their preferential recruitment into the CNS during inflammatory events.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Blood-Brain Barrier / immunology
  • Brain / immunology*
  • Cell Migration Assays
  • Cell Migration Inhibition / immunology
  • Central Nervous System / immunology
  • Encephalomyelitis, Autoimmune, Experimental / blood*
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Female
  • Humans
  • In Vitro Techniques
  • Interferon-gamma / blood
  • Interferon-gamma / immunology*
  • Interleukin-17 / immunology*
  • Interleukin-23 / immunology
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Multiple Sclerosis / blood*
  • Multiple Sclerosis / immunology
  • Multiple Sclerosis, Relapsing-Remitting / blood
  • Multiple Sclerosis, Relapsing-Remitting / immunology
  • T-Lymphocytes / immunology*
  • Th1 Cells / immunology
  • Th2 Cells / immunology


  • Interleukin-17
  • Interleukin-23
  • Interferon-gamma