A recent PLoS One study indicates that the cross-talk between the brain microglia and T cells that follows a microglia’s activation via Toll-like receptors (TLRs) stimulation, results in a shift of the T cells’ profile towards a neurotoxic IL-17+ γδ T cells phenotype.
TLRs are pattern recognition receptors (PRRs) that recognize highly conserved PAMPs derived from viruses, bacteria, fungi, and parasites. In mice, twelve functional TLRs have been identified so far. Some TLRs such as TLR1, TLR2, TLR4, TLR5, and TLR6 are localized to the cell surface and recognize mainly bacterial and fungal components, whereas TLR3, TLR7, TLR8, and TLR9 are primarily localized to endosomal membranes where they sense nucleic acids.
Microglia, the resident macrophages in the brain, express and respond to all known TLRs.
The CD4+ Th17cells were thought to be the major source of IL-17, but we now know that CD8+ T cells, natural killer (NK) cells, and γδ T cells also produce this central pro-inflammatory cytokine. Nowadays, however, γδ T cells are considered the major source of IL-17.
In the PLoS One article, Katja Derkow and colleagues from the Charité University Hospital, Berlin, Germany, have studied the interactions between γδ T cells and microglia activated by TLRs in relation to neuronal damage. They systematically examined the neurotoxic capacity of γδ T cells and the role of microglia and TLRs in this context. γδ T cells express TLR2, TLR7, TLR9, and MyD88.
The study demonstrates that supernatants from microglia activated through TLRs induce neurotoxic IL-17+ γδ T cells.
The authors report that soluble factors, such as IL-1β and IL-23released by TLR-stimulated microglia, the major immune cells of the brain, induce MyD88-dependent activation of γδ T cells. This was indicated by the up-regulation of CD69 and CD25 and by the release of large amounts of IL-17.
They found that the presence of IL-17+ γδ T cells but not naïve γδ T cells, and, importantly, cell-to-cell contact between neurons and T cells, is required for the expression of neurotoxic effects of IL-17+ γδ T cells, as they observed in vitro.
Previous research has indicated a ‘neurotoxic profile’ of IL-17+ γδ T cells in murine models of ischemia/reperfusion and Alzheimer´s disease.
The authors speculate that through the above mechanisms in pathophysiological or clinical settings the entry of γδ T cells into the brain may cause intracellular IL-17 production via contact with microglia, and this effect may not require TLR signaling.
In summary, TLRs-Activated Microglia and soluble factors, including IL-1β and IL-23 secreted from microglia stimulated by TLR-specific ligands, induce MyD88-dependent activation of γδ T cells. Such activated γδ T cells resemble IL-17+ γδ T cells generated by the addition of IL-1β and IL-23
These mechanisms may have important implications for certain neuroinflammatory disorders such as multiple sclerosis, stroke and/or Alzheimer´s disease.