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Pathogenic Microglia Orchestrate Neurotoxic Properties of Eomes-Expressing Helper T Cells.

ABSTRACT: In addition to disease-associated microglia (DAM), microglia with MHC-II and/or IFN-I signatures may form additional pathogenic subsets that are relevant to neurodegeneration. However, the significance of such MHC-II and IFN-I signatures remains elusive. We demonstrate here that these microglial subsets play intrinsic roles in orchestrating neurotoxic properties of neurotoxic Eomes⁺ Th cells under the neurodegeneration-associated phase of experimental autoimmune encephalomyelitis (EAE) that corresponds to progressive multiple sclerosis (MS). Microglia acquire IFN-signature after sensing ectopically expressed long interspersed nuclear element-1 (L1) gene. Furthermore, ORF1, an L1-encoded protein aberrantly expressed in the diseased central nervous system (CNS), stimulated Eomes⁺ Th cells after Trem2-dependent ingestion and presentation in MHC-II context by microglia. Interestingly, administration of an L1 inhibitor significantly ameliorated neurodegenerative symptoms of EAE concomitant with reduced accumulation of Eomes⁺ Th cells in the CNS. Collectively, our data highlight a critical contribution of new microglia subsets as a neuroinflammatory hub in immune-mediated neurodegeneration.

SUBMITTER: Zhang C

PROVIDER: S-EPMC10047905 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Pathogenic Microglia Orchestrate Neurotoxic Properties of Eomes-Expressing Helper T Cells.

Zhang Chenyang C Raveney Ben B Takahashi Fumio F Yeh Tzu-Wen TW Hohjoh Hirohiko H Yamamura Takashi T Oki Shinji S

Cells 20230310 6

In addition to disease-associated microglia (DAM), microglia with MHC-II and/or IFN-I signatures may form additional pathogenic subsets that are relevant to neurodegeneration. However, the significance of such MHC-II and IFN-I signatures remains elusive. We demonstrate here that these microglial subsets play intrinsic roles in orchestrating neurotoxic properties of neurotoxic Eomes<sup>+</sup> Th cells under the neurodegeneration-associated phase of experimental autoimmune encephalomyelitis (EAE ...[more]

PMID: 36980209

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Project description: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.

Dataset Information

Pathogenic Microglia Orchestrate Neurotoxic Properties of Eomes-Expressing Helper T Cells.

Publications

Pathogenic Microglia Orchestrate Neurotoxic Properties of Eomes-Expressing Helper T Cells.

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