Abstract
The central nervous system (CNS) is classically viewed as immune-privileged; however, recent advances highlight interactions between the peripheral immune system and CNS in controlling infections and tissue homeostasis. Tissue-resident memory (TRM) CD8+ T cells in the CNS are generated after brain infections, but it is unknown whether CNS infection is required to generate brain TRM cells. We show that peripheral infections generate antigen-specific CD8+ memory T cells in the brain that adopt a unique TRM signature. Upon depletion of circulating and perivascular memory T cells, this brain signature was enriched and the surveilling properties of brain TRM cells was revealed by intravital imaging. Notably, peripherally induced brain TRM cells showed evidence of rapid activation and enhanced cytokine production and mediated protection after brain infections. These data reveal that peripheral immunizations can generate brain TRM cells and will guide potential use of T cells as therapeutic strategies against CNS infections and neurological diseases.
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Acknowledgements
We thank S. Perlman for critical review and comments on the manuscript and S. Anthony for helpful discussion. We thank J. Fishbaugh, H. Vignes and M. Shey (University of Iowa Flow Cytometry Core Facility) for cell sorting, I. Antoshechkin (California Institute of Technology) and Admera health for RNA-seq. Data herein were obtained from the Flow Cytometry Facility, which is a Carver College of Medicine Core Research Facilities/Holden Comprehensive Cancer Center Core Laboratory at the University of Iowa. This work was supported by grants from the National Institutes of Health (AI42767 to J.T.H., AI114543 to J.T.H. and V.P.B., GM134880 to V.P.B., AI121080 and AI139874 to H.-H.X., T32 AI007343 to S.L.U. and T32 AI007511 to I.J.J.) and the Veteran Affairs BLR&D Merit Review Program (BX002903) to H.-H.X.
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S.L.U. and J.T.H. designed experiments; S.L.U. conducted experiments; S.L.U. and I.J.J. analyzed data; I.J.J., Q.S. and L.L.P. provided technical assistance; V.P.B. and H.-H.X. provided essential reagents and intellectual input and S.L.U. and J.T.H. wrote the manuscript.
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Extended data
Extended Data Fig. 1 Enrichment of antigen specific CD8+ T-cells in the CNS after peripheral immunizations.
a, Gating strategy used to identify CD8+ T cell populations isolated from the CNS. Representative of 3 independent experiments with 4 mice per group.b-e, The proportion of donor OT-I, P14, or OVA tetramer+ cells of live CD8+ T-cells isolated from the Spleen (SP) peripheral blood (PBL) IV+ brain (IV+) or IV– brain (IV–) are graphed after infection with LCMV IV, p values (top to bottom) **** p<0.0001, **** p<0.0001, ****, p<0.0001, ** p=0.0038, and * p=0.0252 (b), DC-OVA-rLM-OVA prime boost IV, p values (top to bottom) **** p<0.0001, **** p<0.0001, *** p=0.0002, *** p=0.0.0004, and *** p=0.0005 (c), DC-GP33-rLM-GP33 prime boost IV, p values (top to bottom) *** p=0.0003, *** p=0.0002, and ****p<0.0001 (d), DC-OVA-VACV-OVA IV, p values (top to bottom) ** p=0.0014, ** p=0.0019, and * p=0.0201 (e). Data represent from 2 independent experiments with 3 mice per group. Graphs show the mean +/- standard deviation with each dot representing an individual mouse. Statistical significance was determined by One-way ANOVA with Tukey’s multiple comparisons test across all the groups using graphpad prism. f, NIH Swiss Webster mice were infected with rLM-OVA IV and the proportion of live CD8+, IV– CD8+ and number of IV– CD8+ cells in the CNS are graphed. Data pooled from 2 independent experiments for a total of 10 mice per group. Graphs show the mean +/- standard deviation with each dot representing an individual mouse. Two-tailed unpaired students T-test were determined using graphpad prism and p values (left to right) * p=0.0458, ** p=0.0048, and * p=0.0216.
Extended Data Fig. 2 Runx3 but not CD103 are required for generation of peripherally induced CNS Trm cells.
a,b, RNA-Seq analysis of memory OT-I cells isolated from SP, IV+, or IV– brains of DC-OVA-rLM-OVA prime boosted mice. Fold change of IV+ vs IV– OT-I cells of corresponding genes identified in Figure 2d (a). Fold change of IV+ vs IV– OT-I cells of 40 different transcription factors associated with Trm or memory CD8+ T cell responses with selected genes indicated (b). RNA samples were isolated from 5 mice pooled per group in duplicate. c, CD103KO and WT mice were DC-OVA-rLM-OVA prime-boosted and brains were harvested at a memory time point. The proportion and numbers of ova-specific CD69+ IV– CD8+ T-cells are plotted. Graphs show the mean +/- standard deviation with each dot representing an individual mouse. Data are representative of 2 individual experiments with 3 mice per group. d,e, WT or CD103KO P14 cells from naïve donors were adoptively transferred into WT CD45.1 hosts prior to LCMV infection IP. At a memory time point, proportion of donor P14 cells were determined and are depicted for WT P14 cells (d) and CD103KO P14 cells (e). Graphs show the mean +/- standard deviation with each dot representing an individual mouse. Data are representative of 2 individual experiments with 5 mice per group. Statistical significance was determined by One-way ANOVA with Tukey’s multiple comparisons test across all the groups using graphpad prism with p values (top to bottom) **** p<0.0001, **** p<0.00001, and **** p<0.0001 (d) and ** p=0.0025, ** p=0.0026, and ** p=0.0033 (e). f,g, WT or Runx3KO P14 cells were adoptively transferred into WT CD45.1 hosts prior to LCMV infection IP. At a memory time point, proportion of donor P14 cells were determined and are depicted for WT P14 cells (f) and Runx3KO P14 cells (g). Graphs show the mean +/- standard deviation with each dot representing an individual mouse. Data are representative of 2 individual experiments with 5 mice per group. Statistical significance was determined by One-way ANOVA with Tukey’s multiple comparisons test across all the groups using graphpad prism with p values (top to bottom) * p=0.0159, and * p=0.0279 (f).
Extended Data Fig. 3 Increased representation of antigen specific CD8+ T-cells after peripheral immunizations is CNS specific.
a-h, Thy1.1 eGFP+ OT-I T-cells were transferred into naïve mice that were DC-OVA-rLM-OVA prime boosted. Representative flow plots (a) showing proportion of OT-I cells of IV+ or IV– Thy1.1 CD8+ T-cells in each organ and cumulative proportion of OT-I cells in each organ, p values (left to right) ** p=0.0028 (b). Proportion of OT-I cells expressing CD103, p values (left to right) *** p=0.00371, * p=0.0100 (c) and CX3CR1, p values (left to right) *** p=0.0001, ** p=0.0027 (d) in IV+ vs IV– brain and meninges. gMFI of CD69, p values (left to right) *** p=0.0005, ** p=0.0013 (e), CXCR6, p values (left to right) **** p<0.0001, *** p=0.0004 (f), and CD49a, p values (left to right) **** p<0.0001, ** p=0.0025 (g) of OT-I cells from IV+ vs IV– brain and meninges are shown. SPADE analysis of OT-I cells from each organ are depicted (h). Markers used to distinguish populations include CD8α, CD11a, CD44, CD49a, CD69, CD103, CXCR6, and CX3CR1. Data are representative of 2 independent experiments with 3 mice per group. Graphs show the mean +/- standard deviation with each dot representing an individual mouse. Two-tailed unpaired l students T-test were determined using graphpad prism.
Extended Data Fig. 4 Peripherally induced CNS Trm cells are resistant to systemic depletion.
a,b, Thy1.1 eGFP+ OT-I T-cells were transferred into naïve mice that were DC-OVA-rLM-OVA prime boosted. At a memory time point, mice were control treated (PBS) or treated with 2, 5, or 10 μg of anti-Thy1.1 Ab IP. One week after depletion, proportions and phenotype of OT-I cells were determined. Representative flow plots gated on live CD8+ cells from Spleen, PBL and IV+ or IV– brain showing proportions of OT-I cells (a) and gMFI of CD69 gated on IV– OT-I cells (b). Graphs show the mean +/- standard deviation with each dot representing an individual mouse. Data are representative of 2 individual experiments with 3 mice per group. Statistical significance was determined by One-way ANOVA with Tukey’s multiple comparisons test across all the groups using graphpad prism with p values (top to bottom) *** p=0.0005, *** p=0.0004, and * p=0.0144. c, Thy1.1 eGFP+ OT-I T-cells were transferred into naïve mice that were DC-OVA-rLM-OVA prime boosted. After memory formation, mice were control treated (PBS) or treated with 2 μg of anti-Thy1.1 Ab IP. One week after depletion, OT-I cells in the CNS were imaged and maximum speed was determined. Graph depicts mean with each dot representing an individual OT-I cell from 71 cells from 12 individual movies (PBS), and 103 cells from 16 individual movies (2 μg). Statistical significance was determined by two-tailed Mann Whitney test using graphpad prism with **** p<0.0001.
Extended Data Fig. 5 Enhanced recall response of peripherally induced brain Trm cells is specific to CNS.
a,b, OT-I T-cells were transferred into recipient mice that were DC-OVA-VACV-OVA prime boosted. At a memory time point, mice were either unchallenged or challenged with rLM-OVA IC and organs were harvested 2 days later and stained for CD25 and intracellular IFN-γ directly ex vivo. Proportion of CD25+, p value **** p<0.0001 (a) and IFN-γ+, p value *** p=0.0004 (b) OT-I cells from each organ are graphed. Graphs show the mean +/- standard deviation with each dot representing an individual mouse. Data are representative of 2 independent experiments with 4 mice per group. Statistical significance was determined by two-tailed unpaired students T-test for each organ using graphpad prism. c-e, P14 T-cells were transferred into recipient mice that were immunized with LCMV IP. At a memory time point, mice were treated with PBS or 2 μg anti-Thy1.1 Ab IP. One week post depletion, mice were challenged with rLM-GP33 IC and organs were harvested 2 days later and stained for CD25 and intracellular IFN-γ directly ex vivo. Proportion of CD25+, p values (left to right) ** p=0.0099, ** p=0.0014 (c), IFN-γ+, p values (left to right) * p=0.0308, ** p=0.0069 (d) and number of IV– P14 cells (e) from the brain are graphed. Graphs show the mean +/- standard deviation with each dot representing an individual mouse. Data are representative of 2 independent experiments with 3 mice per group. Two-tailed unpaired students T-test was determined using graphpad prism.
Extended Data Fig. 6 Peripherally induced brain resident CD8+ T-cells mediate protection against CNS infections.
a, Thy1.1 OT-I cells were transferred into mice and DC-OVA-rLM-OVA prime boosted. After memory formation, these mice and naïve controls were challenged with VSV-OVA IN. Virus titers in brains were determined at day 3 post infection. Data are combined from 2 independent experiments for a total of 10 mice per group. Graph shows the mean +/- standard deviation with each dot representing an individual mouse. Two-tailed unpaired students T-test was determined using graphpad prism where ** p=0.0021. b, Thy1.1 OT-I cells were transferred into recipient mice that were DC-OVA-rLM-OVA prime boosted. After memory formation, mice were treated with PBS or 2 μg anti-Thy1.1 Ab IP. One week after depletion these mice and naïve controls mice were challenged with VSV-OVA IC. Kaplan Meier survival curves depicted. Data from representative experiment with 6 (black), 8 (red), and 9 (blue) mice per group (top to bottom). Graphpad prism used to determine significance using Mantel-Cox test for each group comparing to the Naïve + IC challenge group with p values * p=0.014 (red), and ** p=0.0056 (blue). c,d, Thy1.1 OT-I or P14 cells were transferred into recipient mice that were DC-OVA-rLM-OVA or DC-GP33-rLM-GP33 prime boosted, respectively. After memory formation, mice were treated with PBS or 2 μg anti-Thy1.1 Ab IP. Frequency of OVA or GP33 tetramer positive cells and proportion of transgenic OT-I or P14 T-cells were determined prior to and 5 days post depletion. Representative flow plots (c) and cumulative data (d) of 2 independent experiments with 5 mice per group are shown.
Supplementary information
Supplementary Video 1
Behavior of peripherally induced brain TRM cells. Representative time-lapse video shows dynamics of memory CD8+ T cells through a thinned skull by two-photon laser scanning microscopy of DC-OVA-rLM-OVA immunized mice. eGFP OT-I cells (green) and blood vessels (red) show projections representing z-stacks 80 μm in depth imaged over a 30-min time period. One representative video is shown from 12 movies. Please see Supplementary Video 2 for a second representative video.
Supplementary Video 2
Behavior of peripherally induced brain TRM cells. Representative time-lapse video shows dynamics of memory CD8+ T cells through a thinned skull by two-photon laser scanning microscopy of DC-OVA-rLM-OVA immunized mice. eGFP OT-I cells (green) and blood vessels (red) show projections representing z-stacks 80 μm in depth imaged over a 30-min time period. One representative video is shown from 12 movies. Please see Supplementary Video 1 for a second representative video.
Supplementary Video 3
Behavior of peripherally induced brain TRM cells. Representative time-lapse video shows dynamics of memory CD8+ T-cells through a thinned skull by two-photon laser scanning microscopy of DC-OVA-rLM-OVA immunized mice. eGFP OT-I cells (green), Thy1.1 PE+ OT-I cells (pink) and blood vessels (red) show projections representing z-stacks 80 μm in depth imaged over a 30-min time period. Representative video and cell tracks of eGFP+ cells are depicted. Representative videos are shown from 15 movies.
Supplementary Video 4
Behavior of peripherally induced brain TRM cells. Representative time-lapse video shows dynamics of memory CD8+ T cells through a thinned skull by two-photon laser scanning microscopy of DC-OVA-rLM-OVA immunized mice. eGFP OT-I cells (green), Thy1.1 PE+ OT-I cells (pink) and blood vessels (red) show projections representing z-stacks 80 μm in depth imaged over a 30-min time period. Representative video and cell tracks of Thy1.1+ cells are depicted. Companion video to Supplementary Video 3. Representative video is shown from 15 movies.
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Urban, S.L., Jensen, I.J., Shan, Q. et al. Peripherally induced brain tissue–resident memory CD8+ T cells mediate protection against CNS infection. Nat Immunol 21, 938–949 (2020). https://doi.org/10.1038/s41590-020-0711-8
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DOI: https://doi.org/10.1038/s41590-020-0711-8
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