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

doi:10.1038/s41590-020-0776-4

. 2020 Nov;21(11):1421-1429.

doi: 10.1038/s41590-020-0776-4. Epub 2020 Sep 14.

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

Kalil Alves de Lima^{1

2

3}, Justin Rustenhoven^#^{4

5

6}, Sandro Da Mesquita^#^{4

5}, Morgan Wall^#^{4

5}, Andrea Francesca Salvador^{4

5

6}, Igor Smirnov^{4

5

6}, Guilherme Martelossi Cebinelli^{4

5

7}, Tornike Mamuladze^{4

5

6}, Wendy Baker^{4

5}, Zach Papadopoulos^{4

5

6}, Maria Beatriz Lopes⁸, William Sam Cao⁹, Xinmin Simon Xie⁹, Jasmin Herz^{4

5

6}, Jonathan Kipnis^{10

11

12}

Affiliations

¹ Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, USA. [email protected].
² Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA, USA. [email protected].
³ Department of Pathology and Immunology, Division of Immunobiology, Washington University, St. Louis, MO, USA. [email protected].
⁴ Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, USA.
⁵ Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA, USA.
⁶ Department of Pathology and Immunology, Division of Immunobiology, Washington University, St. Louis, MO, USA.
⁷ Center for Research on Inflammatory Diseases (CRID), Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil.
⁸ Department of Pathology, School of Medicine, University of Virginia, Charlottesville, VA, USA.
⁹ AfaSci Research Laboratories, Redwood City, CA, USA.
¹⁰ Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, USA. [email protected].
¹¹ Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA, USA. [email protected].
¹² Department of Pathology and Immunology, Division of Immunobiology, Washington University, St. Louis, MO, USA. [email protected].

^# Contributed equally.

PMID: 32929273
PMCID: PMC8496952
DOI: 10.1038/s41590-020-0776-4

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

Kalil Alves de Lima et al. Nat Immunol. 2020 Nov.

. 2020 Nov;21(11):1421-1429.

doi: 10.1038/s41590-020-0776-4. Epub 2020 Sep 14.

Authors

Affiliations

¹ Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, USA. [email protected].
² Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA, USA. [email protected].
³ Department of Pathology and Immunology, Division of Immunobiology, Washington University, St. Louis, MO, USA. [email protected].
⁴ Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, USA.
⁵ Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA, USA.
⁶ Department of Pathology and Immunology, Division of Immunobiology, Washington University, St. Louis, MO, USA.
⁷ Center for Research on Inflammatory Diseases (CRID), Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil.
⁸ Department of Pathology, School of Medicine, University of Virginia, Charlottesville, VA, USA.
⁹ AfaSci Research Laboratories, Redwood City, CA, USA.
¹⁰ Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, USA. [email protected].
¹¹ Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA, USA. [email protected].
¹² Department of Pathology and Immunology, Division of Immunobiology, Washington University, St. Louis, MO, USA. [email protected].

^# Contributed equally.

PMID: 32929273
PMCID: PMC8496952
DOI: 10.1038/s41590-020-0776-4

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.

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Figures

**Extended Data Fig. 1. Meningeal γδ17 T cells are long-lived cells with low proliferative capacity in steady state.**
a, Representative contour plot and histogram of the frequency of meningeal TCR β– or TCR γδ– expressing cells on the double negative (DN, CD4^negCD8^neg) T cell population under steady state by flow cytometry. b, Representative histograms of CD62L, CD44, IL-1R and RORγt expression in meningeal and splenic γδ T cells from naïve mice by flow cytometry. c, Representative contour plots of the intracellular staining for IL-17a, IFNγ and IL-22 in γδ T cells (TCR γδ⁺), conventional αβ T cells (TCR β⁺NK1.1^neg) and NK T lymphocytes (TCR β⁺NK1.1⁺) isolated from spleen. d, Graph bars for the frequency of IL-17a, IFNγ and IL-22 for each isolated meningeal T cell subset. **d_i,** Meningeal γδ T cells; **d_ii,** conventional αβ T cells and **d_iii,** NK T lymphocytes (n = 5 per group). One-way ANOVA followed by Bonferroni's multiple comparisons test. e, Absolute number of γδ T cells isolated from dura, enriched subdural meninges (eSDM), choroid plexus or brain parenchyma under homeostasis (n = 5 per group). One-way ANOVA followed by Bonferroni's multiple comparisons test. **f_i,** Gating strategy for the flow analysis of fresh dura sample isolated from humans. Single live cells were gated as CD45⁺ and the γδ T cell frequency was determined in the CD3⁺. **f_ii,** Contour plots of the frequency of γδ T cells isolated from arachnoid or dura mater by flow cytometry (n = 2). **g_i,** Representative dot plots of the percentage of TCR γδ– or αβ– expressing cells obtained from meninges during prenatal stages (around E18.5) or at 8-weeks of age (Adult). **g_ii,** Graph bars of the percentage and **g_iii,** absolute number of γδ T cells. Each pre-natal sample represents a pool of three embryos. Unpaired two-tailed t test. Data are from one single experiment. **h_i,** Representative flow cytometry analysis of γδ T lymphocytes in the blood (top), and meninges (bottom) of CD45.1⁺ and CD45.2⁺ congenic parabiotic pairs joined for 4 weeks (n = 4 per group). **h_ii,** Mean frequency of either CD45.1⁺ or CD45.2⁺ γδ T cells in each parabiotic pair in the blood and meninges. i, WT mice at post-natal day 14 (P14) or j, adult (8 week-old) were injected daily with EdU (i.p., 10 mg/kg) and three days later the proliferating EdU⁺ cells were determined by flow cytometry. **i_i,** Histograms showing the EdU frequency in γδ T cells and CD11b^hi myeloid cells isolated from meninges and spleen of P14 mice. **i_ii,** Graph bars of the percentage of γδ T cells or **i_iii,** CD11b^hi myeloid cells co–expressing EdU. P14 (n = 5 per group). **j_i,** Representative histograms of γδ T lymphocytes and CD11b^hi myeloid cells expressing EdU in meninges and spleen of adult mice. **j_ii,** Graph bars of the percentage of γδ T cells and **j_iii,** CD11b^hi myeloid cells co-expressing EdU. Adult (n = 5 per group). **k_i,** Scheme of the experimental details used to assess the proliferation capacity of meningeal γδ T cells by immunohistochemistry. P14 or adult *Tcrd*^CreERT2:Ai6 mice were injected daily with EdU and tamoxifen (both i.p., 10 mg/kg) and three days later the proliferation of γδ T cells was determined in the whole-mount meninges by confocal microscopy. **k_ii,** Representative images of meningeal whole-mounts isolated from P14 (left) and Adult (right) mice and stained for CD31 (blue) and EdU (red). Arrows indicate γδ T cells proliferating in P14 meninges (TCR δ (ZsGreen)⁺EdU⁺). SSS, superior sagittal sinus. Scale bar, 100 μm. Representative image of one single experiment (n = 5). Data are shown as mean ± s.e.m. and each dot symbol represents individual mouse.

**Extended Data Fig. 2. Meningeal γδ T cells expression profile and additional behavior paradigms using γδ T cell-deficient mice.**
a, Normalized expression of *Tcrgv6* transcripts (Vγ4 chain, Garman nomenclature) in meningeal and splenic γδ T cells obtained by single cell RNA-Seq. b, Graph bars of the TCR Vγ-usage in γδ T cells. **b_i,** Meningeal and **b_ii,** splenic γδ T cells. **b_iii,** Overview of Vγ-chain usage (Vγ1, Vγ2, Vγ3 or others (Vγ4 or Vγ5)). **c_i,** Representative contour plots of the intracellular staining for IL-17a and IFNγ in αβ T cells (TCR β⁺NK1.1^neg) and γδ T lymphocytes (Vγ1, Vγ2, Vγ3–negative or positive fractions) isolated from steady state meninges. **c_ii-v,** Graph bars of the percentage of IL-17a– or IFNγ– producing cells in these different meningeal T cell subsets. One-way ANOVA followed by Bonferroni's multiple comparisons test. d, UMAP projection of γδ T cells colored by the scaled expression of *Slc6a13* (GAT2). e, Average expression of chemokines in CD45⁺ cells isolated from steady state dura mater obtained from public database. f, Representative histogram of the expression of CXCR6-GFP in meningeal T cell subsets. g, Absolute numbers of conventional αβ T cells isolated from CXCR6–sufficient and –deficient mice. Unpaired two-tailed t test. Data represent one independent experiment. **h_i,** Adult *Ccr2*^CreERT2:Ai6 mice were injected daily with tamoxifen (i.p., 10 mg/kg) and three days later meninges, spleen and blood were harvested for FACS analysis. Representative histograms of CCR2-ZsGreen expression in γδ T cells and conventional αβ T lymphocytes by flow cytometry. **h_ii,** Graph bars of the percentage of γδ T cell– and **h_iii,** αβ T cell– expressing CCR2-ZsGreen in spleen, blood and meninges. **h_iv,** Histograms of the expression of CCR2-ZsGreen in meningeal γδ and αβ T lymphocytes. **h_v,** Frequency of CCR2–expressing cells. One-way ANOVA followed by Bonferroni's multiple comparisons test. **i_i,** Representative dot plots of the percentage of meningeal TCR γδ– and TCR β– expressing cells isolated from WT or *Ccr2^−/−* *(Ccr2*^{RFP/ RFP}) mice. **i_ii,** Percentage and **i_iii,** absolute number of meningeal γδ T cells. **i_iv,** Percentage and **i_v** absolute number of meningeal αβ T cells. Unpaired two-tailed t test. **j_i,** Dot plots of the frequency of inflammatory monocytes (CD11b^hiLy6C^hi) isolated from WT or CCR2-deficient mice. **j_ii,** Percentage and **j_iii,** absolute number of meningeal inflammatory monocytes. Data are pooled from two independent experiments with similar results. Unpaired two-tailed t test. k, Social interaction of wild-type and *Tcrd^−/−* mice was assessed in the three-chamber test and the percentage of time investigating either a mouse (social) or an object (inanimate) was calculated. WT (n = 9); *Tcrd^−/−* (n = 11). Two-way ANOVA followed by Bonferroni's multiple comparisons test. **l_i,** For the spatial memory task, WT and γδ T cell-deficient mice were assessed in the training and **l_ii,** novel location tasks of the novel location recognition (NLR) test and the time spent with either a familiar or novel object was determined. WT (n = 8); *Tcrd^−/−* (n = 8). Two-way ANOVA followed by Bonferroni's multiple comparisons test. m, Foraging behavior of wild-type and *Tcrd^−/−* mice assessed in the exploratory and n, foraging phase of the foraging paradigm. Data is pooled from three independent cohorts. WT (n = 18); *Tcrd^−/−* (n = 18); Unpaired two-tailed t test. Data are shown as mean ± s.e.m. and each dot symbol represents individual mouse.

**Extended Data Fig. 3. γδ17 T cells are localized in the meningeal stroma and actively transcribe IL-17a *in vivo*.**
a, Flow cytometry analysis of meninges three days after treatment with 2.5 μg of isotype control or anti-TCR γδ (i.c.m.). **a_i,** Percentage of CD45⁺ live cells. **a_ii,** Frequency of αβ T lymphocytes gated on the CD45⁺ fraction. **a_iii,** Absolute number of CD45⁺ leukocytes, **a_iv,** αβ T cells and **a_v,** γδ T cells in the meninges. Isotype control (n = 3); anti-TCR γδ (n = 3). b, Absolute number of γδ T cells of mice treated as described in a. To bypass their TCR staining, γδ T cells were gated as Thy1.2⁺TCR β^negRORγt⁺ cells. Isotype control (n = 4); anti-TCR γδ (n = 4). c, Levels of TCR γδ expression in splenic γδ T cells three days after treatment with 2.5 μg of isotype control or anti-TCR γδ (i.c.m.). Isotype control (n = 4); anti-TCR γδ (n = 4). d, Expression per cell of IL-17a in Thy1.2⁺TCR β^negRORγt⁺IL-17a⁺ T cells (“visible” and “invisible” γδ T cells). Isotype control (n = 4); anti-TCR γδ (n = 4). **e_i,** WT mice were injected with 2.5 μg of anti-TCR γδ or isotype control (i.c.m.) and seven days later were assessed in the elevated plus maze. Representative track plots of the cumulated movement. **e_ii,** Percentage time spent in the open arms of the maze. Isotype control (n = 10); anti-TCR γδ (n = 10). **f_i,** Representative histogram of the levels of TCR γδ expression in meningeal γδ17 T cells seven days after injection with isotype control or anti-TCR γδ. **f_ii,** Contour plots of the percentage of IL-17a– and IFNγ–producing meningeal T lymphocytes. **f_iii,** Absolute number of meningeal γδ T cells. **f_iv,** Analysis of the TCR γδ MFI (gated on γδ T cells). **f_v,** Graph bars for the percentage of IL-17a–producing meningeal γδ T cells or **f_vi,** αβ T cells. Isotype control (n = 3); anti-TCR γδ (n = 3). g, Homeostatic IL-17a-eGFP expression in meningeal T cell by immunohistochemistry using the IL-17a reporter mice (*Il17a^eGFP/eGFP*). Insets of the superior sagittal sinus (SSS) of meningeal dural whole-mounts showing CD3 (red), IL-17a (eGFP, green) and CD31 (blue) staining in adult mice. White arrows highlight γδ T cells (defined by the CD3 and IL-17a double-staining). Scale bar, 100 μm. Representative image of at least three independent experiments with similar results (n = 3 per experiment). **h_i,** Representative FACS plot of the IL-17a-eGFP expression of meningeal and splenic γδ T cells under steady state. **h_ii,** Graph bars of IL-17a–expressing cells in the meninges or **h_iii,** spleen (n = 3 per group). **i_i,** Representative dot plots of IL-17a-eGFP⁺ meningeal T cells three days after treatment with 2.5 μg of anti-TCR γδ treatment (i.c.m.). To bypass their TCR staining, “visible” and “invisible” γδ T cells were gated as Thy1.2⁺RORγt⁺ cells. **i_ii,** Frequency of IL-17a-eGFP⁺ meningeal γδ17 T cells (defined as Thy1.2⁺RORγt⁺TCR β^neg cells). **i_iii,** IL-17a expression per a cell basis on IL-17a-eGFP–expressing γδ T cells. Isotype control (n = 5); anti-TCR γδ (n = 5). **j_i,** Scheme of the experimental approach used to label intravascular and tissue-localized cells in steady state meninges. WT mice were given 0.25 μg of anti-CD45 (i.v.) and 3 minutes later blood was collected. Animals were perfused, and meninges were harvested for flow cytometry analysis. **j_ii,** Representative dot plots and **j_iii,** Graph bars of either intravascular (i.v. CD45⁺) or tissue-localized (i.v. CD45^neg) γδ T cells (n = 4 per group). k, Representative meningeal coronal section of IL-17a-eGFP reporter mice stained for DAPI (blue), CD31 (white), and CD3 (red). Arrows indicate a T cell expressing IL-17a-eGFP in meningeal stroma. Scale bar, 100 μm. Representative image of one single experiment (n = 5). l, MSD assay of CSF obtained from WT and *Tcrd^−/−* mice. Technical replicate of meninges pooled from WT or *Tcrd^−/−* mice (n = 10 per group). ND, not detected. m, Steady state concentration of plasmatic IL-17a obtained from WT and *Tcrd^−/−* mice by MSD assay (n = 6 per group). Data are shown as mean ± s.e.m. and each dot symbol represents individual mouse. **a-f, h-i, and m,** Unpaired two-tailed t test.

**Extended Data Fig. 4. Pathways and stimuli involved in the activation of meningeal γδ17 T cells.**
a, Stress was induced in IL-17a-eGFP mice by the exposure to electronical foot shock (ES) for seven consecutive days. **a_i,** Representative dot plots of the IL-17a-eGFP expression by meningeal T cells by flow cytometry. **a_ii,** Frequency of IL-17a-eGFP⁺ γδ17 T cells or **a_iii,** conventional αβ T cells. Data are from one single experiment. Naive (n = 5); ES (n = 5). b, Unpredictable chronic mild stress (UCMS) was induced for over eight weeks in WT mice. **b_i,** Representative expression of IL-17a and IFNγ assessed by the intracellular staining following *ex vivo* stimulation. **b_ii,** Percentage of IL-17a– or **b_iii,** IFNγ– producing γδ T cells. Naive (n = 4); UCMS (n = 5). Data are from one single experiment. **c_i,** Percentage of conventional αβ and γδ T cells isolated from meninges of specific pathogen free (SPF) and germ-free mice. **c_ii,** Representative contour plots of the percentage of IL-17a–positive meningeal γδ cells. **c_iii,** Graph bars of the frequency and **c_iv,** absolute number of meningeal γδ T lymphocytes in SPF versus germ-free animals. **c_v,** Analysis of the frequency and **c_vi,** absolute number of meningeal γδ T cell-producing IL-17a. SPF (n = 5); Germ-free (n = 5). **d_i,** Contour plots of the percentage of IL-17a–positive meningeal γδ cells obtained from meninges of untreated (No Abx) or broad-spectrum antibiotics-treated (Abx) animals and assessed by *ex vivo* stimulation. **d_ii,** Graph bars of the frequency and **d_iii,** absolute number of IL-17a–producing meningeal γδ T lymphocytes. No Abx (n = 3); Abx (n = 4). **e_i,** Representative contour plots of IL-17a and IFNγ expression by meningeal γδ T cells 24 h after aryl hydrocarbon receptor (AHR) activation by the endogenous ligand 6-Formylindolo[3,2-b]carbazole (FICZ, 10 ng, i.c.m.). **e_ii,** Analysis of the frequency of IL-17a– and **e_iii,** IFNγ– producing cells assessed by *ex vivo* stimulation. N = 3 per group. **f_i,** Representative dot plots of the percentage of TCR γδ- or αβ-expressing cells obtained from WT or *Il1r1^−/−* mice. **f_ii,** Analysis of the percentage and **f_iii,** absolute number of meningeal γδ T cells. **f_iv,** Graph bars of the frequency and **f_v,** absolute number of meningeal αβ T lymphocytes. WT (n = 5); *Il1r1^−/−* (n = 5). **g_i,** Contour plots of the IL-17a expression by meningeal γδ T cells following the *ex vivo* stimulation by PMA/Ionomycin. **g_ii,** Analysis of the percentage and **g_iii,** absolute number of IL-17a–producing γδ T cells. WT (n = 5); *Il1r1^−/−* (n = 5). **h_i,** Representative dot plots of the percentage of TCR γδ- or αβ-expressing cells obtained from WT or *Il23a^−/−* mice. **h_ii,** Analysis of the frequency and **h_iii,** absolute number of meningeal γδ T cells. **h_iv,** Graph bars of the percentage and **h_v,** absolute number of meningeal αβ T lymphocytes. WT (n = 3); *Il23ra^−/−* (n = 3). **i_i,** Contour plots of the IL-17a and IFNγ expression by meningeal γδ T cells following *ex vivo* stimulation. **i_ii,** Analysis of the percentage and **i_iii,** absolute number of IL-17a–producing γδ T cells. WT (n = 3); *Il23ra^−/−* (n = 3). **j_i,** Representative contour plots of the percentage of IL-17a–eGFP⁺ meningeal T cells seven days after active EAE induction (EAE 7dpi). **j_ii,** Graph bars of the frequency of meningeal γδ T lymphocytes (total TCR γδ⁺ cells), **j_iii,** conventional αβ T cells (TCR β⁺ cells) and **j_iv,** Vγ2⁺ γδ T cells (gated on total γδ T cells). **j_v,** Percentage of IL-17a–eGFP⁺ cells gated on innate-like γδ T cells (Vγ2^neg) and **j_vi,** expression per cell of IL-17a. **j_vii,** Frequency of IL-17a–eGFP⁺ αβ T cells. Naive (n = 4); EAE (n = 5). **k_i,** Representative contour plots of the percentage of IL-17a–eGFP⁺ meningeal T cells 14 days post EAE induction (EAE 14dpi). **k_ii,** Graph bars of the frequency of meningeal γδ T lymphocytes (TCR γδ⁺ cells), **k_iii,** αβ T cells and **k_iv,** Vγ2⁺ γδ T cells (gated on γδ T cells). **k_v,** Percentage of IL-17a–eGFP⁺ cells gated on innate-like γδ T cells (Vγ2^neg) and **k_vi,** expression per cell of IL-17a–eGFP. **k_vii,** Frequency of IL-17a–eGFP⁺ cells in αβ T cells. Naive (n = 4); EAE (n = 4). Data are shown as mean ± s.e.m. and each dot symbol represents individual mouse. **a-k,** Unpaired two-tailed t test.

**Extended Data Fig. 5. Lack IL-17a signaling does not affect social or learning behaviors.**
**a_i,** Representative track plots of the cumulative total distance of *Il17a*^+/− and *Il17a*^−/− mice in the elevated plus maze test. **a_ii,** Percentage of total time spent in the open arms. *Il17a*^+/− (n = 11) and *Il17a*^−/− (n = 10). Unpaired two-tailed t test. b, Representative images of IL-17Ra (green), NeuN (red) and DAPI (blue) staining in the PFC, c, hippocampus and d, cerebellum of WT mice. **b-d,** Representative image of at least three independent experiments with similar results (n = 3 per experiment). Scale bar, 100 μm. e, Expression of *Il17ra* (Cyan) at anterior–posterior (AP) +1.32 mm, f, AP: −2.75 and g, in the cerebellum by *in situ* hybridization. **e-f,** Scale bar, 500 μm. g, Scale bar, 100 μm. *Il17ra* (Cyan) was co-labelled with GABAergic (*Gad2*, green), glutamatergic markers (*Slc17a7*, magenta), and DAPI (blue). **e-g,** Representative image of 5 independent experiments with similar results (n = 3 per experiment).h_i, AAV *Syn1*^Cre was bilaterally injected into the mPFC of WT or *Il17ra*^fl/fl mice. Four weeks later, mPFC slices were prepared for immunohistochemistry analysis. **h_ii** Representative images of IL-17Ra expression in the mPFC of WT or *Il17ra*^fl/fl. **h_ii** Analysis of the efficiency transfection. **h_iii** Coverage of IL-17Ra staining and **hi_v** Quantification of IL-17Ra-positive cells as a fraction of total NeuN⁺ cells. Scale bar, 30 μm. WT (n = 5) and *Il17ra*^fl/fl (n = 5), with 20 slices per mouse. Unpaired two-tailed t test. i, Sociability assay was performed in the three-chamber test and the percentage of time investigating either a mouse (social) or an object (inanimate) was calculated. WT (n = 9) and *Il17ra*^fl/fl (n = 11). Two-way ANOVA followed by Bonferroni's multiple comparisons test. **j_i,** In the fear conditioning paradigm, the percentage of time freezing was evaluated in the context and **j_ii,** cued trial. WT: AAV *Syn1*^Cre (n = 10) and *Il17ra*^fl/fl: AAV *Syn1*^Cre (n = 9). k, AAV *Syn1*^Cre was bilaterally injected into the S1DZ region of WT or *Il17ra*^fl/fl mice. Mice were tested in the elevated plus maze four weeks later. Percentage of total time spent in the open arms of the maze is presented. WT (n = 8) and *Il17ra*^fl/fl (n = 10). Unpaired two-tailed t test. Data represents one single experiment. Data is presented as mean ± s.e.m. and each dot symbol represents individual mouse.

**Extended Data Fig. 6. Neuronal loss of IL-17a signaling changes the transcriptional landscape of mPFC neurons.**
**a_i,** Representative track plots of the cumulative total distance of *Syn1^Cre*, *Il17ra*^fl/fl and *Syn1^Cre:Il17ra*^fl/fl tested in the elevated plus maze test just before nuclei isolation for the scRNA-Seq experiment. **a_ii,** Percentage of total time spent in the open arms. *Il17ra*^fl/fl (n = 5); *Syn1^Cre* (n = 5); and *Syn1^Cre:Il17ra^fl/fl* (n = 4). Data represents one single experiment. *Il17ra*^fl/fl vs. *Syn1^Cre:Il17ra*^fl/fl, P = 0.049; *Syn1^Cre* vs. *Syn1^Cre:Il17ra*^fl/fl; P = 0.011; One-way analysis of variance (ANOVA) followed by Bonferroni's multiple comparisons test. b, Heatmap showing cluster signatures across all mPFC nuclei. Each line represents the scaled expression of the corresponding gene within each nucleus, with more highly expressed genes shown in black. The top five most highly expressed genes from each cluster (compared against all other clusters) are shown. c, Dot plot showing the expression of canonical neuronal subclass markers across each of our Seurat identified clusters. Color represents the scaled average expression and size indicates the percentage of cells within each cluster expressing the gene. **d_i,** Dot plot showing the expression of *Slc17a7, Gad2* and *Il17ra* among 2,590 nuclei isolated from the mouse hippocampus (dentate gyrus). Color represents the scaled average expression and size indicates the percentage of cells within each cluster expressing the gene. **d_ii,** violins show the normalized expression of *Il17ra* within each cell across clusters. e, Bar graph showing the proportion of cells from each sample belonging to each cluster across all mPFC nuclei. f, Violins show the normalized expression of *Il17ra* within each cell across clusters. g, Dot plot showing information about each cluster. In the top row, dot size indicates the total number of cells belonging to the cluster and color indicates the number of differentially expressed genes (DEG) overlapping between *Syn1*^Cre:*Il17ra*^fl/fl vs. *Syn1*^Cre and *Syn1*^Cre:*Il17ra*^fl/fl vs. *Il17ra*^fl/fl (adjusted p value < 0.05, absolute log fold change > 0.1). In the second row, the size of the dot shows the percentage of cells within the cluster expressing *Il17ra* while the color represents the scaled average expression of *Il17ra* across cells in the cluster. h, Heatmaps showing overlapping differentially expressed genes between *Syn1*^Cre:*Il17ra*^fl/fl vs. *Syn1*^Cre and *Syn1*^Cre:*Il17ra*^fl/fl vs. *Il17ra*^fl/fl that are significantly changed in all three layer subsets (far left), the top 50 (based on absolute average log fold change) differentially expressed genes that changed uniquely in Layer II/III (left), and the significantly differentially expressed genes that were uniquely changed in Layer V (right) and Layer VI (far right) with the loss of functional *Il17ra*. Above each heatmap is a pie chart showing the percentage of significantly differentially expressed genes combined across all layers, that belong to each category described (shared, unique to Layer II/III, unique to Layer V, or unique to Layer VI). i, Plots showing the most significantly enriched KEGG pathways based on the set of significantly up- (top) or down- (bottom) regulated genes shared between *Syn1*^Cre:*Il17ra*^fl/fl vs. *Syn1*^Cre and *Syn1*^Cre:*Il17ra*^fl/fl vs. *Il17ra*^fl/fl with colored squares indicating the contribution of each gene to the corresponding enriched pathway.

**Extended Data Fig. 7. IL-17a effects on electrophysiological parameters of mPFC neurons.**
**a-f,** Spontaneous excitatory postsynaptic action potentials (sEPSCs) in the mouse mPFC before and after IL-17a application via bath-application for 20 to 25 minutes (n = 8 neurons). The data points represent sEPSCs frequency or amplitude on a given neuron pre- and post- IL-17a treatment (blue and orange dots respectively – plotted on the right y-axis). Light grey bars represent the frequency or peak amplitude (pA) as % of control in the given neuron (mean and s.e.m., plotted on the left y-axis). **a_i,** Recordings of spontaneous action potentials before (pre) and after (post) IL-17a application (1 ng/mL). **a_ii,** Frequency of spontaneous action potentials pre and post treatment of 1 ng/mL of IL-17a. **b_i,** Representative amplitude of the spontaneous excitatory postsynaptic action potentials in the mouse mPFC before and after application of IL-17a (1 ng/ml) as described before. **b_ii,** Analysis of the peak amplitude. **c_i,** Recordings of spontaneous action potentials before and after IL-17a application (10 ng/mL). **c_ii,** Frequency of spontaneous action potentials pre and post treatment of 10 ng/mL of IL-17a. **d_i,** Representative amplitude of the spontaneous excitatory postsynaptic action potentials before and after application of IL-17a (10 ng/ml). **d_ii,** Analysis of the peak amplitude. **e_i,** Recordings of spontaneous action potentials before and after IL-17a application (100 ng/mL). **e_ii,** Frequency of spontaneous action potentials pre and post treatment of 100 ng/mL of IL-17a. **f_i,** Representative amplitude of the spontaneous excitatory postsynaptic action potentials before and after application of IL-17a (100 ng/ml). **f_ii,** Analysis of the peak amplitude. **g-l,** Spontaneous inhibitory postsynaptic action potentials (sIPSCs) in the mouse mPFC before and after IL-17a application via bath-application for 20 to 25 minutes (n = 8 neurons). **g_i,** Recordings of spontaneous action potentials before and after IL-17a application (1 ng/mL). **g_ii,** Frequency of spontaneous action potentials pre and post treatment of 1 ng/mL of IL-17a. **h_i,** Representative amplitude of the spontaneous inhibitory postsynaptic action potentials before and after application of IL-17a (1 ng/ml). **h_ii,** Analysis of the peak amplitude. **i_i,** Recordings of spontaneous action potentials before and after IL-17a application (10 ng/mL). **i_ii,** Frequency of spontaneous action potentials pre and post treatment of 10 ng/mL of IL-17a. **j_i,** Representative amplitude of the spontaneous inhibitory postsynaptic action potentials before and after application of IL-17a (10 ng/ml). **j_ii,** Analysis of the peak amplitude. **k_i,** Recordings of spontaneous action potentials before and after IL-17a application (100 ng/mL). **k_ii,** Frequency of spontaneous action potentials pre and post treatment of 100 ng/mL of IL-17a. **l_i,** Representative amplitude of the spontaneous inhibitory postsynaptic action potentials before and after application of IL-17a (100 ng/ml). **l_ii,** Analysis of the peak amplitude. **a-l,** Wilcoxon matched-pairs signed rank test.

**Extended Data Fig. 8. IL-17a effects on the evoked action potentials before and after IL-17a treatment.**
**a_i-iii,** Recordings of evoked action potentials in a neuron in the mouse mPFC before (pre) and after (post) IL-17a application (n = 8 neurons). The current injection protocol (−40, 0, 40, 80, 120, 160, 200 pA; 500 ms) is shown in gray underneath the traces. **b_i-iii,** Graphs show the frequency of action potentials (y-axis) in response to different levels of current injection (x-axis) before and after IL-17a bath-application for 20 to 25 minutes. **b_iv,** Graph summarizes the change in frequency pre and post IL-17a treatment. Two-way ANOVA followed by Sidak's multiple comparisons test. Data points and error bars represent the mean and s.e.m., respectively, of n = 8 sets (Pre vs. Post IL-17a treatment).c_i, Scheme of the experimental details to target IL-17a–responding cells. *Fos*^CreERT2:Ai14 mice were treated with 25 ng of IL-17a or saline (i.c.m.) and then given an injection of 4-hydroxytamoxifen (4-OHT, i.p.) one hour later. After seven days, animals were perfused and the mPFC was collected for immunohistochemistry staining and analysis. **c_ii,** Representative photomicrographs from the mPFC of mice injected with IL-17a or saline and stained for a neuronal marker, NeuN (blue), DAPI (red) and showing c-Fos expression (green). **c_iii,** Quantification of c-Fos⁺ cells in the mPFC of stimulated mice. Scale bar, 200 μm. aCSF (n = 5); IL-17a (n = 5). Unpaired two-tailed t test. Representative image of two independent experiments with similar results (n = 5 per experiment). Data is presented as mean ± s.e.m. and each dot symbol represents individual mouse.

**Figure 1. ∣. Dural meninges harbor IL-17 producing (γδ17) T cells.**
a, Mass cytometry analysis of immune cells isolated from meninges of naïve animals. Meningeal T cells (CD3⁺Thy1.2⁺) were clustered as CD4⁺, CD8⁺ or double negative (DN). b, Expression of T cell markers in meningeal γδ T cells, CD4⁺ and CD8⁺ αβ T cells analyzed by mass cytometry (n = 8 pooled mice; each dot represents one cell). Wilcoxon rank sum test with Benjamini Hochberg post hoc adjustments. Data represent one single experiment. NS, not significant. **c_i,** Expression of IL-17a, IFNγ and IL-22 in meningeal γδ T cells, conventional αβ T cells (TCR β⁺NK1.1^neg) and NK T lymphocytes (TCR β⁺NK1.1⁺) by flow cytometric analysis. **c_ii,** Contribution of each isolated population in total IL-17a, IFNγ and IL-22 expression in steady state meninges using backgating analysis. d, Meningeal whole-mounts stained for CD3 (red) and CD31 (blue) showing the presence of γδ T cells (CD3⁺TCR δ (ZsGreen)⁺ cells, in yellow). TS, transverse sinus, SSS, superior sagittal sinus. **d_i,** Scale bar, 200 μm and **d_ii,** 100 μm. Representative image of 3 independent experiments with similar results (n = 3 in each experiment). e, Absolute numbers of meningeal γδ T cells isolated from postnatal animals at P1, P3, P7 and adult (8-week-old) analyzed by flow cytometry. P1 (n = 10); P3 (n = 7); P7 (n = 5); and Adult (n = 5). One-way ANOVA followed by Tukey's multiple comparisons test **f_i,** Ki67 expression in meningeal γδ T cells depicted in e. **f_ii,** Percentage of Ki67^hi γδ T cells isolated from postnatal mice. One-way ANOVA followed by Bonferroni's multiple comparisons test. Data pooled from two independent experiments with similar results. Data are shown as mean ± s.e.m. and each dot symbol represents individual mouse.

**Figure 2. ∣. Functional and molecular characterization of meningeal γδ17 T cells.**
a, UMAP visualization of 1,041 γδ T cells isolated from adult and neonates (P7) colored by each cluster. b, Log normalized expression per cell of hallmark γδ T cell markers, with cells ordered by sample. c, Mean centered, log normalized expression per cell of the top fifty significantly differentially expressed genes (adj. P < 0.05) between adult meningeal and splenic γδ T cells ranked by absolute log fold change. d, Top ten enriched biological processes for the set of significantly differentially expressed genes (adj. P < 0.05) between adult and P7 meningeal γδ T cells using two-sided Fisher’s Exact test with Benjamini Hochberg corrections (FDR < 0.05). e, Expression of chemokine receptors in meningeal and splenic γδ T cells isolated from adult or P7 mice. **f_i,** CXCR6-GFP expression on γδ T cells from adult mice by flow cytometry. **f_ii,** Percentage of CXCR6^hi meningeal or splenic γδ T cells. **f_iii,** Analysis of CXCR6-GFP MFI in γδ T cells. Meningeal (n = 6); Splenic (n = 6). Data is representative of 5 independent experiments. **g_i,** Frequency of TCR γδ- or αβ-expressing cells isolated from CXCR6-sufficient or deficient mice. **g_ii,** Graph bars for the frequency of γδ T cells. *Cxcr6*^+/− (n = 7); *Cxcr6*^−/− (n = 8). Data are pooled from two independent experiments with similar results. **g_iii,** Absolute numbers. *Cxcr6*^+/− (n = 5); *Cxcr6*^−/− (n = 6). Data are pooled from two independent experiments with similar results. **f-g,** Data are shown as mean ± s.e.m. and each dot symbol represents one mouse. Unpaired two-tailed t test.

**Figure 3. ∣. Meningeal γδ17 T cells regulate anxiety-like behavior.**
**a_i,** Cumulative movement of wild type (WT) and γδ T cell-deficient (*Tcrd*^−/−) mice in the elevated plus maze. **a_ii,** Percentage time spent in the open arms of the maze. WT (n = 18); *Tcrd*^−/− (n = 20). Pool of two independent experiments. **b_i,** Cumulated movement of WT and *Tcrd*^−/− animals in the open field test. **b_ii,** Total ambulatory distance in the arena. **b_iii,** Percentage time spent in the center of the arena. WT (n = 8); *Tcrd*^−/− (n = 8). c, WT mice were injected (i.c.m.) with 2.5 μg of anti-TCR γδ or isotype control and three days later were assessed in the elevated plus maze. **c_i,** Cumulated movement of isotype control– or anti-TCR γδ–injected mice. **c_ii,** Percentage time spent in the open arms of the maze. Isotype control (n = 15); anti-TCR γδ (n = 16). Results pooled from two independent experiments. d, WT mice were injected anti-TCR γδ or isotype control and three days later were assessed in the open field task. **d_i,** Cumulative movement in the open field arena. **d_ii,** Total distance traveled. **d_iii,** Percentage time spent in the center of the arena. Isotype control (n = 16); anti-TCR γδ (n = 17). Data were pooled of two independent experiment. **a-d,** Data are expressed as mean ± s.e.m. and each dot symbol represents individual mouse. Unpaired two-tailed t test.

**Figure 4. ∣. Steady state expression of IL-17a by meningeal γδ T cells is partially regulated by TCR engagement and commensal-derived signals.**
**a-b,** WT mice were injected (i.c.m.) with 2.5 μg of anti-TCR γδ or isotype control and their meningeal immunity was analyzed three days later by flow cytometry.a_i, Representative dot plots of meningeal TCR β- or TCR γδ-expressing cells. **a_ii,** Histogram of TCR γδ levels on meningeal γδ T cells. **a_iii,** MFI of TCR γδ. Isotype control (n = 3); anti-TCR γδ (n = 3). **b_i,** Representative contour plots of the percentage of IL-17a– and IFNγ–producing T cells. **b_ii,** Frequency of IL-17a⁺ meningeal γδ T cells. **b_iii,** MFI of IL-17a in IL-17a⁺ meningeal γδ T cells. Isotype control (n = 4); anti-TCR γδ (n = 4). c, Representative contour plots of IL-17a-eGFP expression in fresh meningeal T cell subsets by FACS. P7 (n = 3); Adult (n = 3). d, Steady state concentration of IL-17a in meningeal whole tissue lysates obtained from WT and *Tcrd*^−/− mice by MSD assay. Technical replicate of meninges pooled from WT or *Tcrd*^−/− mice (n = 10 per group); ND, not detected. **e_i,** Percentage of conventional αβ and γδ T cells obtained from meninges of untreated (No Abx) or antibiotics-treated (Abx) animals. **e_ii,** Frequency and **e_iii,** absolute number of meningeal γδ T lymphocytes. No Abx (n = 3); Abx (n = 4). **f_i,** Percentage of IL-17a-eGFP⁺ meningeal γδ T cells from mice treated with Abx. **f_ii,** Frequency of IL-17a-eGFP ⁺ γδ T cells and **f_iii,** IL-17a-eGFP MFI in IL-17a⁺ γδ T cells. No Abx (n = 3); Abx (n = 4). **g_i,** Frequency of IL-17a–eGFP⁺ meningeal T cells four hours after i.p. injection with PBS or LPS (1 mg/kg). **g_ii,** Frequency of total meningeal γδ T lymphocytes, **g_iii,** IL-17a–eGFP⁺ innate-like γδ T cells (Vγ2^neg). **g_iv,** IL-17a–eGFP MFI. PBS (n = 4); LPS (n = 4). Data are expressed as mean ± s.e.m. and each dot symbol represents individual mouse. Unpaired two-tailed t test.

**Figure 5. ∣. IL-17a signaling through cortical neurons regulates anxiety-like behavior.**
**a_i,** Cumulated movement of isotype control– or anti-IL-17a–injected mice in the elevated plus maze 14 h after treatment. **a_ii,** Percentage time spent in the open arms of the plus maze. Isotype control (n = 18) and anti-IL-17a (n = 18). Data were pooled of two independent experiments. b, *Tcrd*^−/− animals were given 25 ng of recombinant IL-17a or artificial CSF (aCSF) via cisterna magna (i.c.m) and after three hours were tested in the elevated plus maze. **b_i,** Total movement in the maze. **b_ii,** Percentage of total time spent in the open arms. aCSF (n = 14) and IL-17a (n = 12). Data were pooled of two independent experiments with similar results. c, Expression of *Il17ra* (Cyan) within the prefrontal cortex regions of naive mice according to cortical layers. ILA, infralimbic cortex; ORBm, medial orbifrontal cortex; PrL, prelimbic cortex; ACAd, dorsal anterior cingulate cortex. Scale bar, 500 μm. Representative image of 5 independent experiments (n = 3 in each experiment). d, *Il17ra* (Cyan) expression on GABAergic (*Gad2*, green) and glutamatergic neurons (*Slc17a7*, magenta) in the mouse mPFC (top) or hippocampus (bottom). DAPI (blue). Scale bar, 100 μm. Representative image of 3 independent experiments with similar results (n = 3 in each experiment). **e_i,** Experimental approach used to ablate the IL-17a signaling in mPFC neurons. AAV *Syn1*^Cre was bilaterally injected into the mPFC of WT or *Il17ra*^fl/fl mice. Mice were tested in the elevated plus maze four weeks later. **e_ii,** Total movement in the maze. **e_iii,** Percentage of total time spent in the open arms of the maze. WT: AAV *Syn1*^Cre (n = 10) and *Il17ra*^fl/fl: AAV *Syn1*^Cre (n = 9). Data are expressed as mean ± s.e.m. and each dot symbol represents individual mouse. Unpaired two-tailed t test.

**Figure 6. ∣. Neuronal IL-17a signaling shapes the transcriptional landscape of mPFC neurons.**
a, Schematic of the experimental approach used to perform single-nuclei RNA-Seq from mPFC neurons in the absence of neuronal IL-17a signaling. **b_i,** UMAP projection of nuclei isolated from the mPFC colored by cluster membership. **b_ii,** UMAP projection indicating subpopulations of neurons based on expression of cortical layer, excitatory, and inhibitory genetic markers. c, UMAP projection colored by the expression of *Il17ra*. d, Overlap among cortical layers in significantly differentially expressed genes (DEG) found between both *Syn1*^Cre:*Il17ra*^fl/fl vs. *Syn1*^Cre and *Syn1*^Cre:*Il17ra*^fl/fl vs. *Il17ra*^fl/fl based on the layers identified in **b_ii**. e, Heatmap of DEG between both *Syn1*^Cre:*Il17ra*^fl/fl vs. *Syn1*^Cre and *Syn1*^Cre:*Il17ra*^fl/fl vs. *Il17ra*^fl/fl in Layer II /III. f, Significantly enriched gene ontology (GO) terms for the set of significantly up (i)- or down- (ii) regulated genes in *Syn1*^Cre:*Il17ra*^fl/fl compared to both *Syn1*^Cre and *Il17ra*^fl/fl in Layer II/III. Color indicating the Benjamini-Hochberg adjusted P value and dot size indicating the number of genes contributing to the enrichment of the term.

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Comment in

IL-17a-mediated anxiety.
Minton K. Minton K. Nat Rev Immunol. 2020 Nov;20(11):647. doi: 10.1038/s41577-020-00453-3. Nat Rev Immunol. 2020. PMID: 32934354 No abstract available.
IL-17: good fear no tears.
Rua R, Pujol N. Rua R, et al. Nat Immunol. 2020 Nov;21(11):1315-1316. doi: 10.1038/s41590-020-0792-4. Nat Immunol. 2020. PMID: 32958929 No abstract available.

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References

1. Choi GB et al. The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science 351, 933–939 (2016). - PMC - PubMed
1. Chen C et al. IL-17 is a neuromodulator of Caenorhabditis elegans sensory responses. Nature 542, 43–48 (2017). - PMC - PubMed
1. Miller AH & Raison CL The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat. Rev. Immunol 16, 22–34 (2016). - PMC - PubMed
1. 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). - PubMed
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[1] Choi GB et al. The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science 351, 933–939 (2016). - PMC - PubMed

[2] Choi GB et al. The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science 351, 933–939 (2016). - PMC - PubMed

[3] Chen C et al. IL-17 is a neuromodulator of Caenorhabditis elegans sensory responses. Nature 542, 43–48 (2017). - PMC - PubMed

[4] Chen C et al. IL-17 is a neuromodulator of Caenorhabditis elegans sensory responses. Nature 542, 43–48 (2017). - PMC - PubMed

[5] Miller AH & Raison CL The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat. Rev. Immunol 16, 22–34 (2016). - PMC - PubMed

[6] Miller AH & Raison CL The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat. Rev. Immunol 16, 22–34 (2016). - PMC - PubMed

[7] 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). - PubMed

[8] 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). - PubMed

[9] Derecki NC et al. Regulation of learning and memory by meningeal immunity: a key role for IL-4. J. Exp. Med 207, 1067–1080 (2010). - PMC - PubMed

[10] Derecki NC et al. Regulation of learning and memory by meningeal immunity: a key role for IL-4. J. Exp. Med 207, 1067–1080 (2010). - PMC - PubMed

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

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

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