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Cited by 416T-cell and B-cell ImmunologyNeuroinflammation and Neurodegeneration MechanismsTryptophan and brain disorders

Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons

Open access
Alves de Lima, Kalil, Rustenhoven, Justin, Da Mesquita, Sandro, Wall, Morgan, Salvador, Andrea Francesca, Smirnov, Igor, Martelossi Cebinelli, Guilherme, Mamuladze, Tornike +7 more·2020·Nature Immunology
DOI 10.1038/s41590-020-0776-4PMC PMC8496952
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Abstract

Interleukin (IL)-17a has been highly conserved during evolution of the vertebrate immune system and widely studied in contexts of infection and autoimmunity. Studies suggest that IL-17a promotes behavioral changes in experimental models of autism and aggregation behavior in worms. Here, through a cellular and molecular characterization of meningeal γδ17 T cells, we defined the nearest central nervous system–associated source of IL-17a under homeostasis. Meningeal γδ T cells express high levels of the chemokine receptor CXCR6 and seed meninges shortly after birth. Physiological release of IL-17a by these cells was correlated with anxiety-like behavior in mice and was partially dependent on T cell receptor engagement and commensal-derived signals. IL-17a receptor was expressed in cortical glutamatergic neurons under steady state and its genetic deletion decreased anxiety-like behavior in mice. Our findings suggest that IL-17a production by meningeal γδ17 T cells represents an evolutionary bridge between this conserved anti-pathogen molecule and survival behavioral traits in vertebrates. IL-17a is an evolutionarily conserved cytokine with behavior-modulating roles in the central nervous system. Kipnis and colleagues characterize a population of meningeal γδ17 T cells that use IL-17a to elicit anxiety-like behavior through cortical glutamatergic neurons.

AI snapshot

Written from the paper’s full text.

TL;DR

Meningeal γδ17 T cells in the dura are a homeostatic CNS-associated source of IL-17a, and their TCR-dependent IL-17a production regulates anxiety-like behavior in mice. IL-17a acts on cortical glutamatergic neurons via IL-17Ra, shaping mPFC neuronal transcription and excitatory synaptic transmission.

Key findings

  • Dural meninges harbor γδ17 T cells that express RORγt, CCR6, CD44, CD69, and high CXCR6; upon ex vivo stimulation they comprised more than 95% of the potential IL-17a source in the meningeal space. They seed meninges postnatally, are tissue-resident by parabiosis, and show low adult self-renewal.
  • Reducing meningeal γδ17 T cell function or IL-17a signaling decreased anxiety-like behavior: Tcrd−/− mice spent more time in elevated plus maze open arms and open field center; i.c.m. anti-TCR γδ or anti-IL-17a decreased anxiety-like behavior; i.c.m. IL-17a in Tcrd−/− mice increased anxiety-like behavior.
  • IL-17Ra was expressed in cortical glutamatergic neurons, with low to no expression in hippocampus. Deleting neuronal Il17ra in mPFC decreased anxiety-like behavior and altered over 300 genes in mPFC neurons, enriched for GABA-benzodiazepine activity; IL-17a increased spontaneous excitatory postsynaptic current frequency but not amplitude.
  • Commensal-derived signals and TCR engagement partially regulated IL-17a transcription by meningeal γδ17 T cells; stress paradigms, EAE, IL-1R deficiency, and IL-23 deficiency did not alter IL-17a production in the reported assays.

Methods

  • Mouse dural meninges, other CNS borders, and human autopsy dura/arachnoid (n = 2) were analyzed by CyTOF, flow cytometry, whole-mount immunostaining, parabiosis, EdU/Ki67 proliferation assays, and scRNA-Seq of sorted γδ T cells from P7 and adult mice.
  • Behavioral testing included elevated plus maze, open field, novel location recognition, contextual fear conditioning, three-chamber sociability, and foraging; targeted manipulations used i.c.m. anti-TCR γδ, anti-IL-17a, recombinant IL-17a, AAV Syn1Cre into mPFC of Il17rafl/fl mice, sNuc-Seq of NeuN+ mPFC nuclei, and whole-cell patch-clamp recordings.
  • Statistical comparisons used two-tailed unpaired t tests, one-way or two-way ANOVA with multiple-comparison tests, and differential expression/enrichment analyses as described.

Limitations

  • The paper states that peripheral leak of i.c.m. antibodies cannot rule out a contribution of blood-derived IL-17a to behavioral readouts; whether transcriptional changes causally connect to behavior and which downstream pathways follow basal neuronal IL-17a signaling remain unresolved.
  • The paper notes uncertainty about how commensal-derived signals activate meningeal γδ17 T cells and whether this depends on TCR signaling, and it reports an off-target effect of anti-TCR γδ treatment on splenic γδ T cells.
  • Evident from the text: human data are limited to n = 2 autopsy samples; CSF IL-17a was below technical detection limits; most behavior studies used male mice, although key findings were also tested in female mice.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41590-020-0776-4

Cites

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Statistics

Nothing to recompute.

Claims the paper makes

0 of 30 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Tcrd−/− mice spend more time in the center of the open field arena than their wild type counterparts.

    “In agreement with the elevated plus maze findings, the Tcrd−/− mice spent more time in the center of the arena than their WT counterparts (Fig. 3b), supporting the notion that mice lacking γδ T cells show decreased basal levels of vigilance, which we interpreted as decreased anxiety-behavior.”
    Quote in the paperSubstantial claim
  • Findingown data

    In vivo anti-TCR γδ administration is associated with internalization of TCR γδ without actual loss of meningeal γδ T cells.

    “In vivo administration of anti-TCR γδ monoclonal antibodies was associated with internalization of TCR γδ, without actual loss of the meningeal γδ T cells (Fig. 4a, Extended Data Fig. 3a-b), similar to what has been previously shown in the intestine18.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Nielsen, M. M., Witherden, D. A. & Havran, W. L. γδ T cells in homeostasis and host defence of epithelial barrier tissues. Nat. Rev. Immunol. 17, 733–745 (2017). source

      Not checked in the free run.

  • Findingown data

    γδ T cell-deficient mice exhibit significantly increased exploration time in the open arms of the elevated plus maze compared to wild type littermates.

    “However, γδ T cell-deficient mice exhibited significantly increased exploration time in the open arms of the elevated plus maze test when compared to their wild type (WT) littermates (Fig. 3a).”
    Quote in the paperSubstantial claim
  • Findingown data

    Gene set enrichment analysis shows enrichment of cell cycle and DNA replication biological processes in P7 meningeal γδ17 T cells.

    “Our results demonstrated enrichment of biological processes that participate in cell cycle and DNA replication in the P7 meningeal γδ17 T cells (Fig. 2d).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Ccr2−/− mice display elevated T cell frequencies and numbers in the meningeal compartment.

    “In addition to CXCR6, ~20% of meningeal γδ17 T cells also expressed CCR2 (Fig. 2e, Extended Data Fig. 2h), however, Ccr2−/− mice displayed elevated T cell frequencies and numbers in the meningeal compartment (Extended Data Fig. 2i-j).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 36
  • Classified as probably not a substantial claim. 27
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data

    Similar γδ T-cell populations are detected in fresh autopsy samples of human dura, with fewer cells present in the arachnoid mater.

    “Similar γδ T-cell populations were also detected in fresh autopsy samples of human dura, with fewer cells present in the arachnoid mater (Extended Data Fig. 1f).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Meningeal γδ17 T cells exhibit high homeostatic proliferation at early postnatal periods (P1-7) and very low proliferation rates in adult mice.

    “Ki67 staining revealed that meningeal γδ17 T cells exhibited high homeostatic proliferation at early postnatal periods (P1-7) yet maintained very low proliferation rates in adult mice (Fig. 1f).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    γδ T cells display progressive seeding of the dural meninges from postnatal day three, with substantial numbers present by day seven.

    “Flow cytometry analysis revealed that γδ T cells were virtually absent in prenatal dural meninges (Extended Data Fig. 1g) but displayed a progressive seeding from postnatal day three with substantial numbers present by day seven (Fig. 1e).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The cluster distribution of γδ T cells is partitioned into two main subsets based on meningeal or splenic origin, supporting maximal similarity between meningeal γδ T cells regardless of age.

    “Nonetheless, this cluster distribution was clearly partitioned into two main subsets, based on meningeal or splenic origin (Fig. 2a), thereby supporting maximal similarity between meningeal γδ T cells regardless of the age of the mice.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Single-cell RNA-sequencing of dural and splenic γδ T cells from P7 or adult mice revealed 10 clusters, demonstrating heterogeneity within the γδ T-cell lineage.

    “Uniform manifold approximation and projection (UMAP) for dimensionality reduction revealed 10 clusters, demonstrating heterogeneity within the γδ T-cell lineage (Fig. 2a).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    CXCR6 deficiency also decreases the number of conventional αβ T cells in the meningeal compartment.

    “Interestingly, the number of conventional αβ T cells, was also decreased by CXCR6 deficiency (Extended Data Fig. 2g).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    About 20% of meningeal γδ17 T cells express CCR2.

    “In addition to CXCR6, ~20% of meningeal γδ17 T cells also expressed CCR2 (Fig. 2e, Extended Data Fig. 2h), however, Ccr2−/− mice displayed elevated T cell frequencies and numbers in the meningeal compartment (Extended Data Fig. 2i-j).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Anti-TCR γδ administration decreases the percentage of meningeal IL-17a-producing γδ T cells and the cell-based production of IL-17a.

    “Administration of anti-TCR γδ decreased the percentage of meningeal IL-17a-producing γδ T cells as well as the cell-based production of IL-17a (Fig. 4b, Extended Data Fig. 3d).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Tcrd−/− mice show no deficit in spatial memory task, social preference, or foraging behavior.

    “Profiling of Tcrd−/− mice in a battery of behavioral tests revealed no deficit in spatial memory task, social preference, or foraging behavior (Extended Data Fig. 2k-n).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    More than 99% of blood-circulating γδ T cells are stained with intravenous anti-CD45, while only 1-2% of meningeal γδ17 T cells are labelled, suggesting localization to dural parenchyma.

    “More than 99% of blood-circulating γδ T cells were stained with the i.v. anti-CD45, while only 1-2% of meningeal γδ17 were labelled (Extended Data Fig. 3j), suggesting their localization to dural parenchyma.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    TCR γδ expression, IL-17a production, and anxiety levels return to normal one week after anti-TCR γδ treatment.

    “Importantly, TCR γδ expression, IL-17a production, and anxiety levels returned to normal one week later, which indicates γδ T-cell receptor recycling, antigen engagement, and reciprocal regulation of anxiety-like behaviors (Extended Data Fig. 3e-f).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Dural meninges are enriched in γδ T cells expressing IL-17a upon ex vivo stimulation, comprising more than 95% of the potential cytokine source in the meningeal space.

    “Mirroring their RORγt expression, the dural meninges demonstrated enrichment in γδ T cells expressing IL-17a upon ex vivo stimulation, which comprised more than 95% of the potential cytokine source in the meningeal space (Fig. 1c, Extended Data Fig. 1c-d).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Anti-TCR γδ treatment has an off-target effect on splenic γδ T cells.

    “It is important to note that in addition to its primarily meningeal specificity, an off-target effect of anti-TCR γδ treatment was also observed in splenic γδ T cells (Extended Data Fig. 3c).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Meningeal γδ17 T cells share many functional genes with their IL-17a-producing counterparts residing in other tissues.

    “While meningeal γδ17 T cells shared many functional genes (such as Maf, Blk and Cd163l1) with their IL-17a-producing counterparts residing in other tissues, the functional roles of a sizeable number of genes remains unexplored (Fig. 2c).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    Meningeal γδ17 T cells are long-lived cells with low proliferative capacity in steady state.

    “Meningeal γδ17 T cells are long-lived cells with low proliferative capacity in steady state.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At steady state, IL-17Ra expression is found in multiple other brain areas, but low to no expression is detected in the hippocampus.

    “Importantly, at steady state, IL-17Ra expression was found in multiple other brain areas (Extended Data Fig. 5b-g), but low to none expression was detected in the hippocampus (Fig. 5d).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Lack of IL-17a signaling does not affect social or learning behaviors.

    “Lack IL-17a signaling does not affect social or learning behaviors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Single-nuclei RNA-sequencing from the mouse hippocampus reveals very low to none neuronal Il17ra expression, supporting preferential IL-17Ra expression in cortical glutamatergic neurons.

    “sNuc-Seq performed from samples isolated from the mouse hippocampus revealed very low to none neuronal Il17ra expression (Extended Data Fig. 6d), supporting the preferential IL-17Ra expression in cortical glutamatergic neurons.”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    Il17ra is expressed in the mPFC and cerebellum and co-localizes with GABAergic and glutamatergic markers.

    “Il17ra (Cyan) was co-labelled with GABAergic (Gad2, green), glutamatergic markers (Slc17a7, magenta), and DAPI (blue).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Shared Nearest Neighbor (SNN) clustering optimized with the Louvain algorithm, as implemented by the Seurat FindNeighbors and FindClusters functions, resulted in 10 clusters and a modularity score of 0.8313.

    “Shared Nearest Neighbor (SNN) clustering optimized with the Louvain algorithm, as implemented by the Seurat FindNeighbors and FindClusters functions, resulted in 10 clusters and a modularity score of 0.8313.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    CSF levels of IL-17a are below the technical limits of detection, while plasma levels are comparable between groups.

    “It is noteworthy that CSF levels of IL-17a were below the technical limits of detection (Extended Data Fig. 3l), however its plasma levels were comparable between groups (Extended Data Fig. 4m).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    IL-17Ra is expressed in the PFC, hippocampus, and cerebellum of WT mice.

    “Representative images of IL-17Ra (green), NeuN (red) and DAPI (blue) staining in the PFC, c, hippocampus and d, cerebellum of WT mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    IL-17a is detected in dural meningeal homogenates from wild type but not Tcrd−/− mice, suggesting IL-17a is likely released by γδ17 T cells in the meningeal stroma.

    “IL-17a detection in dural meningeal homogenates from WT but not Tcrd−/− mice further suggests that IL-17a is likely released by γδ17 T cells in the meningeal stroma (Fig. 4d).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    γδ17 T cells are localized in the meningeal stroma and actively transcribe IL-17a in vivo.

    “γδ17 T cells are localized in the meningeal stroma and actively transcribe IL-17a in vivo.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Over 300 differentially expressed genes are observed between groups, with the great majority enriched in neurons annotated for cortical layers II/III.

    “Overall, we did not find any striking difference in the representation of individual clusters (Extended Data Fig. 6e), but we observed over 300 DEG, in which the great majority were enriched in neurons annotated for the cortical layers II/III (Fig. 6d, Extended Data Fig. 6f-g).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    IL-17a regulates social behavior in maternal immune activation models.

    “Previously described non-immune properties of IL-17 included (i) the regulation of social behavior in MIA models1,23”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Miller, A. H. & Raison, C. L. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat. Rev. Immunol. 16, 22–34 (2016). source

      Not checked in the free run.

    • cites [23] Hu, B. et al. γδ T cells and adipocyte IL-17RC control fat innervation and thermogenesis. Nature 578, 610–614 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Commensal bacteria are necessary for expansion and activation of γδ T cells via direct or indirect pathways.

    “While the identity of TCR ligands for γδ T cells have been obscure, some reports suggest that commensal bacteria are necessary for their expansion and activation, via direct or indirect pathways20.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Reed, M. D. et al. IL-17a promotes sociability in mouse models of neurodevelopmental disorders. Nature 577, 249–253 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Meningeal γδ17 T cells have a transcriptional signature and higher activation status during early postnatal stages.

    “In summary, these findings reveal a transcriptional signature for meningeal γδ17 T cells and corroborate their higher activation status during early postnatal stages.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    IL-17a regulates body temperature.

    “Previously described non-immune properties of IL-17 included (i) the regulation of social behavior in MIA models1,23, (ii) body temperature24,25, and (iii) neuromodulation in Caenorhabditis elegans2.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [24] Chen, C. et al. IL-17 is a neuromodulator of Caenorhabditis elegans sensory responses. Nature 542, 43–48 (2017). source

      Not checked in the free run.

    • cites [25] Ivanov, I. I. et al. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe 4, 337–349 (2008). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Abnormal behaviors, including decreased anxiety-like behavior in the elevated plus maze, have been reported in the absence of microbiota.

    “Abnormal behaviors have also been reported in the absence of microbiota, including decreased anxiety-like behavior in the elevated plus maze21.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Choi, G. B. et al. The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science 351, 933–939 (2016). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Alleviated anxiety-like behavior has previously been linked to the lack of microbiota.

    “Alleviated anxiety-like behavior has been previously linked to the lack of microbiota21.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Choi, G. B. et al. The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science 351, 933–939 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    γδ T cells populate the meninges at perinatal stages and may be maintained by low-rate self-renewal.

    “Taken together, these data indicate that γδ T cells populate the meninges at perinatal stages and may be maintained by low-rate self-renewal.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Embryonic IL-17Ra signaling on S1DZ results in social impairment, while the same signaling during adulthood promotes sociability.

    “While embryonic IL-17Ra signaling on S1DZ results in social impairment1, same signaling during adulthood promotes sociability23.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Miller, A. H. & Raison, C. L. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat. Rev. Immunol. 16, 22–34 (2016). source

      Not checked in the free run.

    • cites [23] Hu, B. et al. γδ T cells and adipocyte IL-17RC control fat innervation and thermogenesis. Nature 578, 610–614 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Loss of IL-17Ra in the somatosensory cortex (S1DZ) has previously been implicated in neuronal IL-17a signaling to mediate social abnormalities.

    “Loss of IL-17Ra in the somatosensory cortex (S1DZ), previously implicated in neuronal IL-17a signaling to mediate social abnormalities1,23, also decreased anxiety levels of animals (Extended Data Fig. 5k)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Miller, A. H. & Raison, C. L. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat. Rev. Immunol. 16, 22–34 (2016). source

      Not checked in the free run.

    • cites [23] Hu, B. et al. γδ T cells and adipocyte IL-17RC control fat innervation and thermogenesis. Nature 578, 610–614 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    γδ17 T cells are situated in the dural meninges and constitute the nearest CNS-related potential source of IL-17a under steady state conditions.

    “Collectively, these findings indicate that γδ17 T cells are situated in the dural meninges and constitute the nearest CNS-related potential source of IL-17a under steady state conditions.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    IL-17a has neuromodulatory properties in Caenorhabditis elegans.

    “Previously described non-immune properties of IL-17 included (i) the regulation of social behavior in MIA models1,23, (ii) body temperature24,25, and (iii) neuromodulation in Caenorhabditis elegans2.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Alves de Lima, K., Rustenhoven, J. & Kipnis, J. Meningeal immunity and its function in maintenance of the central nervous system in health and disease. Annu. Rev. Immunol. 38, 597–620 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The medial prefrontal cortex is an integral structure for threat interpretations and regulates subcortical responses to threatening stimuli.

    “An integral structure for threat interpretations is the medial prefrontal cortex (mPFC), which regulates subcortical responses to threatening stimuli14.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Louveau, A. et al. CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature. Nat. Neurosci. 21, 1380–1391 (2018). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Meningeal γδ T cells are linked to short-term memory via IL-17a signaling in glial cells.

    “More recently, meningeal γδ T cells were linked to short-term memory via IL-17a signaling in glial cells7.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Vantourout, P. & Hayday, A. Six-of-the-best: unique contributions of γδ T cells to immunology. Nat. Rev. Immunol. 13, 88–100 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Meningeal γδ17 T cells actively express IL-17a under steady state and TCR engagement partially regulates this process.

    “Taken together, these findings demonstrate that meningeal γδ17 T cells are actively expressing IL-17a under steady state and that TCR engagement partially regulates this process.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Experimental groups were blinded and randomly assigned before the start of experimentation and remained blinded until all data were collected.

    “Experimental groups were blinded and randomly assigned before the start of experimentation and remained blinded until all data were collected.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Freezing behavior was manually scored by a blinded experimenter using Etholog v.2.2 software.

    “Mice behavior was recorded by a digital video camera mounted above the conditioning chamber and freezing was manually scored by a blinded experimenter using the Etholog v.2.2 software.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Most of the paper's behavior studies were performed on male mice, and its key findings were also tested in female mice.

    “Most of our behavior studies were performed on male mice, and our key findings were also tested in female mice.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The probe DapB was used as a negative control.

    “The probe DapB (310043, Advanced Cell Diagnostics) was used as a negative control.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Sample sizes were chosen on the basis of a power analysis using estimates from previously published experiments.

    “Sample sizes were chosen on the basis of a power analysis using estimates from previously published experiments.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Spontaneous IPSCs were observed as upward spikes that could be blocked by the addition of 10 μM bicuculline.

    “Spontaneous IPSCs were observed as upward spikes that could be blocked by the addition of 10 μM bicuculline.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Homeostatic neuronal IL-17a signaling shapes the transcriptional landscape of mPFC neurons and might be correlated with the behavioral changes in the anxiety state of the organism.

    “Altogether, these observations demonstrate that homeostatic neuronal IL-17a signaling shapes the transcriptional landscape of mPFC neurons and might be correlated with the behavioral changes in the anxiety state of the organism.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Meningeal γδ17 T cells are pre-programmed to quickly respond independently of microbiota and inflammatory signals (IL-1β and IL-23), but pathogen/commensal-derived signals affect their basal transcription of IL-17a.

    “Taken together, these findings suggest that meningeal γδ17 T cells are pre-programmed to quickly respond independently of microbiota and inflammatory signals (IL-1β and IL-23), but pathogen/commensal-derived signals affect their basal transcription of IL-17a.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationreasoning

    In highly pathogenic ancestral environments, evolutionary conservation of tissue sentinels such as meningeal γδ17 T cells may have allowed organisms to respond rapidly to environmental stresses while also adapting to additional physiological processes, such as host alertness and exposure to external threats.

    “In the highly pathogenic ancestral environments, evolutionary conservation of tissue sentinels such as meningeal γδ17 T cells may have allowed organisms to respond rapidly to environmental stresses while also adapting to additional physiological processes, such as host alertness and exposure to external threats including predators and pathogens.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: IL-17a is highly conserved across the evolution of the vertebrate immune system.

  • May combine two claims.

    Interpretationown data

    Basal neuronal IL-17a signaling contributes to proper neurotransmitter release from excitatory presynaptic terminals of mPFC neurons, thus regulating anxiety-like traits in mouse.

    “These results suggest that the basal neuronal IL-17a signaling contributes to proper neurotransmitter release from excitatory presynaptic terminals of mPFC neurons, thus regulating anxiety-like traits in mouse.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Each antibody was validated on meningeal tissue, titrated and optimal concentrations used in the panel.

    “Each antibody was validated on meningeal tissue, titrated and optimal concentrations used in the panel.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Results from different genders were never mixed.

    “We never mix the results from different genders.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    The finding that commensal-derived signals regulate IL-17a transcription by meningeal γδ17 cells is in disagreement with previously published work, which may have missed commensal participation by assessing IL-17a expression by ex vivo stimulation.

    “This is in disagreement with the previously published work7, which may have missed the commensal participation by assessing IL-17a expression by ex vivo stimulation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Vantourout, P. & Hayday, A. Six-of-the-best: unique contributions of γδ T cells to immunology. Nat. Rev. Immunol. 13, 88–100 (2013). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Spontaneous EPSCs were observed as downward spikes that could be blocked by the addition of 30 μM DNQX.

    “Spontaneous EPSCs were observed as downward spikes that could be blocked by the addition of 30 μM DNQX.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Quantitative analysis of c-Fos imaging measurements was performed blinded with the FIJI package for ImageJ, using the cell counter.

    “Quantitative analysis of c-Fos imaging measurements was performed blinded with the FIJI package for ImageJ, using the cell counter.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The behavioral phenotype observed in the absence of neuronal IL-17Ra is complex and is not limited to the prefrontal cortex.

    “Loss of IL-17Ra in the somatosensory cortex (S1DZ), previously implicated in neuronal IL-17a signaling to mediate social abnormalities1,23, also decreased anxiety levels of animals (Extended Data Fig. 5k), indicating that the behavioral phenotype observed in the absence of neuronal IL-17Ra is complex and is not limited to prefrontal cortex.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] Miller, A. H. & Raison, C. L. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat. Rev. Immunol. 16, 22–34 (2016). source

      Not checked in the free run.

    • cites [23] Hu, B. et al. γδ T cells and adipocyte IL-17RC control fat innervation and thermogenesis. Nature 578, 610–614 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Meningeal γδ17 T cells are bona fide tissue-localized cells and the nearest CNS-associated source of IL-17a under homeostasis.

    “Collectively, these results demonstrate that meningeal γδ17 T cells are bona fide tissue-localized cells and the nearest CNS-associated source of IL-17a under homeostasis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Genetic deletion of neuronal IL-17Ra from the mouse mPFC recapitulates the behavioral changes observed in γδ T cell-deficient mice and supports a direct effect of IL-17a in neurons.

    “Genetic deletion of neuronal IL-17Ra from the mouse mPFC, an integral structure for threat interpretations, recapitulated the behavioral changes observed in γδ T cell-deficient mice and supported a direct effect of IL-17a in neurons.”
    Quote in the paperSubstantial claim
57 of 57

  • The paper relies on this without support.

    γδ T cells are the first T cells generated during embryonic development and rapidly seed peripheral tissues where specialized subsets are maintained for life as tissue-resident cells.

    “γδ T cells are the first T cells generated during embryonic development and rapidly seed peripheral tissues where specialized subsets are maintained for life as tissue-resident cells.”

  • The paper relies on this without support.

    IL-17a is highly conserved across the evolution of the vertebrate immune system.

    “IL-17a is highly conserved across the evolution of the vertebrate immune system, probably owing to its key role in fighting infections at barrier sites.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Under pathological conditions, IL-17 can be secreted by several other cells in the CNS in addition to Th17 cells.

    “This is largely because under pathological conditions, IL-17 can be secreted by several other cells in the CNS in addition to Th17 cells.”

    From Chronic stress-induced depression requires the recruitment of peripheral Th17 cells into the brain (2022) · cites this paper as [71]

    The Results section, “Steady state meninges harbor a CNS-associated source of IL-17a” (page unavailable), identifies meningeal γδ T cells as an IL-17a source distinct from Th17 cells. The paper establishes this chiefly under steady-state conditions; it does not establish that several other CNS cells secrete IL-17 under pathological conditions. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Meningeal resident γδ17 T cells express RORγt and have been implicated in regulating anxiety-like behaviour and short-term memory via IL-17 signalling.

    “Particularly, meningeal resident γδ17 T cells, which express RORγt as well, have been recently implicated in regulating anxiety-like behaviour and short-term memory via IL-17 signalling [70, 71].”

    From Chronic stress-induced depression requires the recruitment of peripheral Th17 cells into the brain (2022) · cites this paper as [71]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Intravenous anti-CD45 dose differs tenfold

    Minor

    The Methods specify 2.5 μg of intravenous anti-CD45 antibody, whereas the caption for the same vascular-labeling procedure specifies 0.25 μg.

  • Plasma IL-17a result cites the wrong extended-data figure

    Minor

    The Results cite Extended Data Fig. 4m for plasma IL-17a levels, but the supplied captions place that measurement in Extended Data Fig. 3m; the Fig. 4 caption has no panel m.

  • IL-23-deficient mouse genotype changes within figure caption

    Minor

    Extended Data Fig. 4 identifies the mice in panel h as Il23a−/−, but labels the comparison group for panels h and i as Il23ra−/−. These denote different genes.

3 of 3

Cites

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Authors
Alves de Lima, K., Rustenhoven, J., Da Mesquita, S., Wall, M., Salvador, A. F., Smirnov, I., Martelossi Cebinelli, G., Mamuladze, T., Baker, W., Papadopoulos, Z., Lopes, M. B., Cao, W. S., Xie, X. S., Herz, J., & Kipnis, J.
Affiliations
  • Washington University in St. Louis (US)
  • University of Virginia (US)
  • AfaSci (United States) (US)
Corresponding author
Kipnis, Jonathan
ORCID
Venue
Nature Immunology
Publisher
Springer Science and Business Media LLC
Published
2020-09-14
Volume
21
Issue
11
Pages
1421-1429
ISSN
  • 1529-2908 (ISSN-L)
  • 1529-2916
DOI
10.1038/s41590-020-0776-4
PMC
PMC8496952
OpenAlex
W3085338548
Semantic Scholar
fe0d578f1ef4501abf2a39f565167ef67ea6ae5e
Cited by
416
References
42
Citations by year
2026: 63 · 2025: 69 · 2024: 67 · 2023: 69 · 2022: 90 · 2021: 53 · 2020: 5
FWCI
19.15
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
U.S. Department of Health & Human Services | NIH | National Center for Complementary and Integrative Health (AT010416)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Keywords
IL-17A, anxiety-like behavior, IL-17 receptor, CXCR6, T cell receptor engagement, commensal microbiota, neuroimmune regulation
MeSH terms
Animals, Anxiety, Behavior, Animal, Cerebral Cortex, Disease Models, Animal, Dura Mater, Gene Expression Regulation, Meninges, Neurons, Signal Transduction, T-Lymphocyte Subsets, Receptors, Antigen, T-Cell, gamma-delta, Mice, Knockout, Interleukin-17, Gene Expression Profiling, Cell Proliferation, Mice, Transcriptome

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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