Preferential recruitment of interferon‐γ–expressing T H 17 cells in multiple sclerosis

Objective There is substantial evidence supporting the role of interferon (IFN)‐γ–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‐γ–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‐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 H 17 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 H 1‐ and the T H 17‐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 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‐γ + T H 17 lymphocytes in the pathology of MS and EAE and their preferential recruitment into the CNS during inflammatory events. Ann Neurol 2009;66:390–402