γδ T cell subsets play opposing roles in regulating experimental autoimmune encephalomyelitis

gamma delta T cells are resident in cerebrospinal fluid and central nervous system (CNS) lesions of multiple sclerosis (MS) patients, but as multifaceted cells exhibiting innate and adaptive characteristics, their function remains unknown. Previous studies in experimental autoimmune encephalomyelitis (EAE) are contradictory and identified these cells as either promoting or suppressing disease pathogenesis. This study examines distinct gamma delta T cell subsets during EAE and indicates they mediate differential functions in CNS inflammation and demyelination resulting in pathogenesis or protection. We identified two gamma delta subsets in the CNS, V gamma 1(+) and V gamma 4(+), with distinct cytokine profiles and tissue specificity. Anti-gamma delta T cell receptor (TCR) monoclonal antibody (mAb) administration results in activation and downregulation of surface TCR, rendering the cells undetectable, but with opposing effects: anti-V gamma 4 treatment exacerbates disease whereas anti-V gamma 1 treatment is protective. The V gamma 4(+) subset produces multiple pro-inflammatory cytokines including high levels of IL-17, and accounts for 15-20% of the interleukin-17 (IL-17) producing cells in the CNS, but utilize a variant transcriptional program than CD4(+) Th17 cells. In contrast, the V gamma 1 subset produces CCR5 ligands, which may promote regulatory T cell differentiation. gamma delta T cell subsets thus play distinct and opposing roles during EAE, providing an explanation for previous reports and suggesting selective targeting to optimize regulation as a potential therapy for MS. (C) 2014 Elsevier Inc. All rights reserved.