Transcription factor T-bet drives the pathogenesis of T_H17-mediated neuroinflammation

Emergingdata demonstrate that exposure to pro-inflammatory cytokines IL-12 and IL-23 convertsnon-pathogenic IL-17A-producing CD4⁺ T_H17 cells intopathogenic effectors, though the molecular mechanism remains undefined. Here, we show that T-bet, a transcription factor normally associated with IFN-γ-producing T_H1 cell differentiation, is an IL-23-induced critical regulator of pathogenic T_H17 cells. Using the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS), we report that IL-23-treated T-bet-deficient T_H17 cells were not pathogenic and failed to induce neuroinflammation. We found that T-bet expression in T_H17 cells was required to disrupt the blood-brain barrier (BBB) upon migration to the CNS. Following in vivo reactivation, T-bet-sufficient T_H17 cells co-expressed IFN-γ and GM-CSF cytokines, upregulated expression of myelo monocytic-specific chemokines (Ccl1, Ccl3, Ccl4 and Ccl5), and attracted neutrophils, inflammatory monocytes and dendritic cells to the CNS. Conversely, T-bet-deficient T_H17 cells failed to cross the BBB and invade CNS tissue, showing decreased cytokine and chemokine expression and reduced myelomonocyte recruitment. Interestingly, pharmacological BBB disruption via adjuvant administration bypassed the requirement for T-bet expression in T_H17 cells, resulting in disease induction by T-bet-deficient T_H17 cells. Collectively, these data demonstrate that autoreactive T_H17 cells permeabilize the blood-brain barrier in a T-bet-dependent manner, resulting in a cascade of damaging inflammatory infiltrates.