Preferential recruitment of interferon-γ-expressing T_H17 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_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). Methods: 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. Results: 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. Interpretation: 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.