Abstract
BackgroundInterleukin-17 (IL-17) acts as a key regulator in central nervous system (CNS) inflammation. γδ T cells are an important innate source of IL-17. Both IL-17+ γδ T cells and microglia, the major resident immune cells of the brain, are involved in various CNS disorders such as multiple sclerosis and stroke. Also, activation of Toll-like receptor (TLR) signaling pathways contributes to CNS damage. However, the mechanisms underlying the regulation and interaction of these cellular and molecular components remain unclear.ObjectiveIn this study, we investigated the crosstalk between γδ T cells and microglia activated by TLRs in the context of neuronal damage. To this end, co-cultures of IL-17+ γδ T cells, neurons, and microglia were analyzed by immunocytochemistry, flow cytometry, ELISA and multiplex immunoassays.ResultsWe report here that IL-17+ γδ T cells but not naïve γδ T cells induce a dose- and time-dependent decrease of neuronal viability in vitro. While direct stimulation of γδ T cells with various TLR ligands did not result in up-regulation of CD69, CD25, or in IL-17 secretion, supernatants of microglia stimulated by ligands specific for TLR2, TLR4, TLR7, or TLR9 induced activation of γδ T cells through IL-1β and IL-23, as indicated by up-regulation of CD69 and CD25 and by secretion of vast amounts of IL-17. This effect was dependent on the TLR adaptor myeloid differentiation primary response gene 88 (MyD88) expressed by both γδ T cells and microglia, but did not require the expression of TLRs by γδ T cells. Similarly to cytokine-primed IL-17+ γδ T cells, IL-17+ γδ T cells induced by supernatants derived from TLR-activated microglia also caused neurotoxicity in vitro. While these neurotoxic effects required stimulation of TLR2, TLR4, or TLR9 in microglia, neuronal injury mediated by bone marrow-derived macrophages did not require TLR signaling. Neurotoxicity mediated by IL-17+ γδ T cells required a direct cell-cell contact between T cells and neurons.ConclusionTaken together, these results point to a crucial role for microglia activated through TLRs in polarization of γδ T cells towards neurotoxic IL-17+ γδ T cells.
Highlights
Introduction γδ T cells are unconventionalT cells, present at approximately 1–4% in murine blood and secondary lymphoid tissue, whose T cell receptor (TCR) is composed of γ and δ chains instead of the conventional αβ TCR
While direct stimulation of γδ T cells with various Toll-like receptor (TLR) ligands did not result in up-regulation of CD69, CD25, or in IL-17 secretion, supernatants of microglia stimulated by ligands specific for TLR2, TLR4, TLR7, or TLR9 induced activation of γδ T cells through IL-1β and IL-23, as indicated by up-regulation of CD69 and CD25 and by secretion of vast amounts of IL-17
Neurotoxicity mediated by IL-17+ γδ T cells required a direct cell-cell contact between T cells and neurons. These results point to a crucial role for microglia activated through TLRs in polarization of γδ T cells towards neurotoxic IL-17+ γδ T cells
Summary
T cells, present at approximately 1–4% in murine blood and secondary lymphoid tissue, whose T cell receptor (TCR) is composed of γ and δ chains instead of the conventional αβ TCR. These cells feature innate-like characteristics such as localization to non-lymphoid organs, activation in absence of TCR stimulation, and rapid release of inflammatory molecules upon their activation. The myeloid differentiation primary response gene 88 (MyD88) is a central adaptor molecule in TLR signal transduction It contains the Toll-interleukin-1 (IL-1) receptor (TIR) domain, a conserved cytoplasmic region of *200 amino acids shared by TLR and IL-1R family members [6]. The mechanisms underlying the regulation and interaction of these cellular and molecular components remain unclear
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