There is substantial evidence supporting the role of interferon (IFN)‐γ–producing T helper (T_H) 1 and interleukin (IL)‐17–expressing T_H17 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‐γ–expressing T_H17 lymphocytes in MS and EAE, and study their recruitment into the central nervous system (CNS).

Human T_H17 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.

We demonstrate that in response to IL‐23, human memory lymphocytes expand into a T_H17 phenotype, with a subpopulation of cells simultaneously expressing IFN‐γ and IL‐17. We note that lymphocytes obtained from the blood of relapsing MS patients have an increased propensity to expand into IFN‐γ–producing T_H17 cells and identify numerous T lymphocytes coexpressing IL‐17 and IFN‐γ in brain tissue of MS patients. We also find lymphocytes expressing both the T_H1‐ and the T_H17‐associated transcription factors RORγt and T‐bet, in situ and in vitro. We further provide in vitro and in vivo evidence that IFN‐γ⁺ T_H17 lymphocytes preferentially cross the human BBB and accumulate in the CNS of mice during the effector phase of EAE.

Our data underscore the involvement of IFN‐γ⁺ T_H17 lymphocytes in the pathology of MS and EAE and their preferential recruitment into the CNS during inflammatory events. Ann Neurol 2009;66:390–402