TLRs-Activated Microglia T Cells Neurotoxic IL-17

TLRs-Activated Microglia Polarizes γδ T Cells towards a Neurotoxic IL-17+ γδ T Cell Phenotype

TLRs-Activated Microglia – Neurotoxic IL-17

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.

There are three types of glial cells (see cover image): first, the star-shaped cells, astrocytes, support communication between neurons. Second, oligodendrocytes speed up the transmission of information, allowing neurons to communicate quickly. Lastly, the smallest type of glial cell is known as microglia, which has begun to draw more attention in recent years. Although microglia only make up about 10% of all brain cells, these inconspicuous members of our brain work to create a stable environment by keeping our brain clean and healthy, thus allowing neurons to perform their vitally important functions.

Microglia, the resident macrophages in the brain, express and respond to all known TLRs.

After the discovery of T helper (Th)17 cells in 2005, their main product, IL-17, has rapidly emerged as a key player in the pathogenesis of several autoimmune/inflammatory diseases. This includes rheumatoid arthritis, psoriasis, inflammatory bowel disease, systemic lupus erythematosus and multiple sclerosis (MS).

The CD4+ Th17 cells 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.

γδ T cells represent a distinct population of T cells, approximately 1–5% of the total lymphocytes, and appear to be ‘specialized’ in a rapid ‘innate-like’ immune response and a first line of defense from various infections via their expression of TLRs. TLRs are protein receptors that respond and recognize highly conserved components from viruses, bacteria, fungi, and parasites.

Cytokines released from antigen presenting cells (APCs) activated by TLRs such as IL-1β, IL-18, and IL-23 play a crucial role in the induction of IL-17 in the absence of TCR stimulation in γδ T cells. TLR4-deficient γδ T cells display reduced IL-17 and IFN-γ responses during experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis. Neurons can be targeted directly by CD8+ and CD4+ T cells in infection, neuroinflammatory and neurodegenerative diseases

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-23 released 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.

Source: PLoS One. 2015; 10(8):e0135898. doi: 10.1371/journal.pone.0135898. eCollection 2015.
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Cover Image Credit (left panel):  In the brain, there are 3 main glial cell types that support neurons to keep our brain healthy: a) astrocytes help communication between neurons, b) oligodendrocytes create conditions for the information to be transmitted faster, and c) microglia act as the immune system of the brain. From: Microglia: The protectors of the brain. Public Domain.