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Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons
Open accessAbstract
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.
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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.
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71 Own result · 23 Not checked yet · 16 Own interpretation · 10 Own method · 1 No basis given
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In the paper
“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.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > Meningeal γδ17 T cells control anxiety-like behaviors.
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“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.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > Homeostatic activation of meningeal γδ17 T regulates anxiety-like behavior.
What the sources say
- Not checked yetcites [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
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In the paper
“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).”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > Meningeal γδ17 T cells control anxiety-like behaviors.
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“Our results demonstrated enrichment of biological processes that participate in cell cycle and DNA replication in the P7 meningeal γδ17 T cells (Fig. 2d).”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > Molecular diversity and transcriptional landscape of meningeal γδ17 T cells.
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In the paper
“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).”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > CXCR6 is highly expressed in meningeal γδ17 T cells.
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In the paper
“In splenic populations the genes Cd27, Id3 and Tbx21, all characteristic of IFNγ-producing γδ T cells, were overrepresented (Fig. 2b).”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > Molecular diversity and transcriptional landscape of meningeal γδ17 T cells.
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In the paper
“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).”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > γδ17 T cells populate meninges shortly after birth and are maintained by slow self-renewal.
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In the paper
“we generated a tamoxifen-inducible TcrdCreERT2:Ai6 γδ T cell reporter line and through co-staining with anti-CD3, observed a high concentration of these cells restricted to regions along the dural sinuses (Fig. 1d).”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > Steady state meninges harbor a CNS-associated source of IL-17a.
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In the paper
“Consistent with its steady-state expression, we observed a CD3+IL-17a-eGFP+ population by immunofluorescence, mainly confined to regions of the dural sinuses (Extended Data Fig. 3g), which mirrored the γδ T cell distribution (Fig. 1d).”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > Homeostatic activation of meningeal γδ17 T regulates anxiety-like behavior.
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“Using publicly available scRNA-Seq data8, we found that Cxcl16 (the ligand for CXCR6) was highly expressed in dural-resident myeloid cells (Extended Data Fig. 2e), indicating a potential receptor-ligand axis for its dural recruitment, retention and/or activation.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > CXCR6 is highly expressed in meningeal γδ17 T cells.
What the sources say
- Not checked yetcites [8] Zhou, Y. et al. Deletion of the γ-aminobutyric acid transporter 2 (GAT2 and SLC6A13) gene in mice leads to changes in liver and brain taurine contents. J. Biol. Chem. 287, 35733–35746 (2012). source
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In the paper
“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).”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > Steady state meninges harbor a CNS-associated source of IL-17a.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > γδ17 T cells populate meninges shortly after birth and are maintained by slow self-renewal.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > γδ17 T cells populate meninges shortly after birth and are maintained by slow self-renewal.
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > Molecular diversity and transcriptional landscape of meningeal γδ17 T cells.
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In the paper
“Uniform manifold approximation and projection (UMAP) for dimensionality reduction revealed 10 clusters, demonstrating heterogeneity within the γδ T-cell lineage (Fig. 2a).”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > Molecular diversity and transcriptional landscape of meningeal γδ17 T cells.
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“Interestingly, the number of conventional αβ T cells, was also decreased by CXCR6 deficiency (Extended Data Fig. 2g).”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > CXCR6 is highly expressed in meningeal γδ17 T cells.
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“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).”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > CXCR6 is highly expressed in meningeal γδ17 T cells.
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > Homeostatic activation of meningeal γδ17 T regulates anxiety-like behavior.
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > Meningeal γδ17 T cells control anxiety-like behaviors.
plain- Asserted: passes — The authors put it forward as true.
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“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.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > Homeostatic activation of meningeal γδ17 T regulates anxiety-like behavior.
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In the paper
“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).”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > Homeostatic activation of meningeal γδ17 T regulates anxiety-like behavior.
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > Steady state meninges harbor a CNS-associated source of IL-17a.
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > Homeostatic activation of meningeal γδ17 T regulates anxiety-like behavior.
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“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).”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > Molecular diversity and transcriptional landscape of meningeal γδ17 T cells.
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“Meningeal γδ17 T cells are long-lived cells with low proliferative capacity in steady state.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Extended Data
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“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).”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > IL-17a signaling through cortical neurons regulates anxiety-like behavior.
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“Lack IL-17a signaling does not affect social or learning behaviors.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Extended Data
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“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.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > IL-17a signaling shapes the transcriptional landscape of mPFC neurons.
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“Il17ra (Cyan) was co-labelled with GABAergic (Gad2, green), glutamatergic markers (Slc17a7, magenta), and DAPI (blue).”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Extended Data
plaincorrelationaln = 5- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Methods > Dimensionality reduction and clustering of γδ T cells.
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In the paper
“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).”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > Homeostatic activation of meningeal γδ17 T regulates anxiety-like behavior.
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Representative images of IL-17Ra (green), NeuN (red) and DAPI (blue) staining in the PFC, c, hippocampus and d, cerebellum of WT mice.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Extended Data
plainn = 3- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > Homeostatic activation of meningeal γδ17 T regulates anxiety-like behavior.
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“γδ17 T cells are localized in the meningeal stroma and actively transcribe IL-17a in vivo.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Extended Data
plaincorrelationaln = 4- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > IL-17a signaling shapes the transcriptional landscape of mPFC neurons.
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Previously described non-immune properties of IL-17 included (i) the regulation of social behavior in MIA models1,23”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Discussion
What the sources say
- Not checked yetcites [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 yetcites [23] Hu, B. et al. γδ T cells and adipocyte IL-17RC control fat innervation and thermogenesis. Nature 578, 610–614 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > Molecular mediators regulating IL-17a production by meningeal γδ17 T cells.
What the sources say
- Not checked yetcites [20] Reed, M. D. et al. IL-17a promotes sociability in mouse models of neurodevelopmental disorders. Nature 577, 249–253 (2020). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In summary, these findings reveal a transcriptional signature for meningeal γδ17 T cells and corroborate their higher activation status during early postnatal stages.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > Molecular diversity and transcriptional landscape of meningeal γδ17 T cells.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Discussion
What the sources say
- Not checked yetcites [24] Chen, C. et al. IL-17 is a neuromodulator of Caenorhabditis elegans sensory responses. Nature 542, 43–48 (2017). source
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Abnormal behaviors have also been reported in the absence of microbiota, including decreased anxiety-like behavior in the elevated plus maze21.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > Molecular mediators regulating IL-17a production by meningeal γδ17 T cells.
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Alleviated anxiety-like behavior has been previously linked to the lack of microbiota21.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Discussion
What the sources say
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together, these data indicate that γδ T cells populate the meninges at perinatal stages and may be maintained by low-rate self-renewal.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > γδ17 T cells populate meninges shortly after birth and are maintained by slow self-renewal.
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“While embryonic IL-17Ra signaling on S1DZ results in social impairment1, same signaling during adulthood promotes sociability23.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Discussion
What the sources say
- Not checked yetcites [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 yetcites [23] Hu, B. et al. γδ T cells and adipocyte IL-17RC control fat innervation and thermogenesis. Nature 578, 610–614 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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)”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > IL-17a signaling through cortical neurons regulates anxiety-like behavior.
What the sources say
- Not checked yetcites [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 yetcites [23] Hu, B. et al. γδ T cells and adipocyte IL-17RC control fat innervation and thermogenesis. Nature 578, 610–614 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > Steady state meninges harbor a CNS-associated source of IL-17a.
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Discussion
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“An integral structure for threat interpretations is the medial prefrontal cortex (mPFC), which regulates subcortical responses to threatening stimuli14.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > IL-17a signaling through cortical neurons regulates anxiety-like behavior.
What the sources say
- Not checked yetcites [14] Louveau, A. et al. CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature. Nat. Neurosci. 21, 1380–1391 (2018). source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“More recently, meningeal γδ T cells were linked to short-term memory via IL-17a signaling in glial cells7.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Discussion
What the sources say
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > Homeostatic activation of meningeal γδ17 T regulates anxiety-like behavior.
boostedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Experimental groups were blinded and randomly assigned before the start of experimentation and remained blinded until all data were collected.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Methods > Behavior.
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Methods > Contextual Fear Conditioning (CFC) test.
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Most of our behavior studies were performed on male mice, and our key findings were also tested in female mice.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Methods > Behavior.
plain- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The probe DapB (310043, Advanced Cell Diagnostics) was used as a negative control.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Methods > In situ hybridization.
plain- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Sample sizes were chosen on the basis of a power analysis using estimates from previously published experiments.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Methods > Behavior.
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Spontaneous IPSCs were observed as upward spikes that could be blocked by the addition of 10 μM bicuculline.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Methods > Whole-patch clamp recording.
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > IL-17a signaling shapes the transcriptional landscape of mPFC neurons.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > Molecular mediators regulating IL-17a production by meningeal γδ17 T cells.
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
- Rests on an assumption: IL-17a is highly conserved across the evolution of the vertebrate immune system.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > IL-17a signaling shapes the transcriptional landscape of mPFC neurons.
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Each antibody was validated on meningeal tissue, titrated and optimal concentrations used in the panel.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Methods > Mass cytometry.
plain- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We never mix the results from different genders.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Methods > Behavior.
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Discussion
What the sources say
- Not checked yetcites [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
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Spontaneous EPSCs were observed as downward spikes that could be blocked by the addition of 30 μM DNQX.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Methods > Whole-patch clamp recording.
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Quantitative analysis of c-Fos imaging measurements was performed blinded with the FIJI package for ImageJ, using the cell counter.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Methods > Confocal microscopy.
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > IL-17a signaling through cortical neurons regulates anxiety-like behavior.
What the sources say
- Not checked yetcites [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 yetcites [23] Hu, B. et al. γδ T cells and adipocyte IL-17RC control fat innervation and thermogenesis. Nature 578, 610–614 (2020). source
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > Homeostatic activation of meningeal γδ17 T regulates anxiety-like behavior.
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
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.”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Methods > Labelling of the vascular compartment.
“mice were injected i.v. with 2.5 μg of eFluor 450-conjugated anti-CD45 antibody (eBioscience, clone 30-F11) 3 min before euthanasia.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Extended Data
“WT mice were given 0.25 μg of anti-CD45 (i.v.) and 3 minutes later blood was collected.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Results > Homeostatic activation of meningeal γδ17 T regulates anxiety-like behavior.
“however its plasma levels were comparable between groups (Extended Data Fig. 4m).”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Extended Data
“m, Steady state concentration of plasmatic IL-17a obtained from WT and Tcrd−/− mice by MSD assay (n = 6 per group).”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Extended Data
“hi, Representative dot plots of the percentage of TCR γδ- or αβ-expressing cells obtained from WT or Il23a−/− mice.”
§ Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons > Extended Data
“WT (n = 3); Il23ra−/− (n = 3).”
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Resolving the mysteries of brain clearance and immune surveillance
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Metadata
- 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
- Published
- 2020-09-14
- Volume
- 21
- Issue
- 11
- Pages
- 1421-1429
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- 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
- green
- europepmc.org
- 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
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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.
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