T-bet expression in NK cells is critical in the pathogenicity of Th17-induced neuroinflammation

Abstract

Abstract Experimental autoimmune encephalomyelitis (EAE) is a murine model for multiple sclerosis (MS) in which self-reactive CD4+ T cells induce autoimmune inflammation in the central nervous system (CNS). Although mice deficient in the transcription factor T-bet are resistant to EAE disease, the mechanism by which T-bet deficiency confers protection against EAE is poorly understood. Here, we demonstrate that EAE induction via the adoptive transfer of 2D2 TCR-transgenic (CNS Ag-specific) Th17 cells requires T-bet expression in both the donor T cells and a host immune cell subset(s) within the CNS. While T-bet-expressing 2D2 Th17 cells induced severe neuropathology upon transfer into wild-type recipient mice, T-bet-deficient recipients were highly resistant to EAE induction by 2D2 Th17 adoptive transfer. Lineage-specific deletions of T-bet in either the endogenous T cells or dendritic cells of host mice had no effect on EAE induction. Strikingly, the deletion of T-bet specifically in natural killer (NK) cells significantly abrogated EAE disease, indicating a critical pathogenic role for T-bet expression in CNS-infiltrating NK cells. Resistance to EAE was similarly observed following the systemic depletion of NK cells in recipient mice. Although T-bet-deficient NK cells infiltrating the CNS did not show intrinsic defects in classical pro-inflammatory effector functions, preliminary data suggests that T-bet regulates the trafficking of NK cells into the CNS as well as their activation state within the CNS. Elucidating the mechanisms by which T-bet expression in NK cells and CD4+ T cells regulates EAE disease pathogenicity could ultimately lead to novel and improved therapies against clinical MS disease.