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Mucosal-associated invariant T cells restrict reactive oxidative damage and preserve meningeal barrier integrity and cognitive function

Nature Immunology volume 23, pages 1714–1725 (2022)Cite this article

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Abstract

Increasing evidence indicates close interaction between immune cells and the brain, revising the traditional view of the immune privilege of the brain. However, the specific mechanisms by which immune cells promote normal neural function are not entirely understood. Mucosal-associated invariant T cells (MAIT cells) are a unique type of innate-like T cell with molecular and functional properties that remain to be better characterized. In the present study, we report that MAIT cells are present in the meninges and express high levels of antioxidant molecules. MAIT cell deficiency in mice results in the accumulation of reactive oxidative species in the meninges, leading to reduced expression of junctional protein and meningeal barrier leakage. The presence of MAIT cells restricts neuroinflammation in the brain and preserves learning and memory. Together, our work reveals a new functional role for MAIT cells in the meninges and suggests that meningeal immune cells can help maintain normal neural function by preserving meningeal barrier homeostasis and integrity.

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Fig. 1: MAIT cells are present in the meninges.
Fig. 2: MAIT cells express genes encoding secreted antioxidant molecules.
Fig. 3: MAIT cells have high levels of ROS and expression of antioxidant molecules is required for optimal survival and growth of MAIT cells.
Fig. 4: MAIT cells help preserve meningeal barrier integrity.
Fig. 5: MAIT cells repress ROS accumulation and preserve expression of junctional molecules by leptomeningeal cells.
Fig. 6: MAIT cells repress microgliosis at homeostasis.
Fig. 7: MAIT cells are required for optimal cognitive function at homeostasis.

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Data availability

ScRNA-seq data have been deposited in the National Center for Biotechnology Information’s Gene Expression Omnibus under accession nos. GSE189656 and GSE189661. Source data are provided with this paper.

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Acknowledgements

We thank A. Rabson, H. Ching Lin, P. Jiang and Z. Pang for critical discussion and technical help. This work was supported by the US NIH (grant nos. R01HL137813, R01AG057782 and R01HL155021 to Q.Y.), the NIH Intramural Research Programs (to D.B.M., Y.B. and A.B.) and support to the Child Health Institute of New Jersey from the Robert Wood Johnson Foundation (grant no. 74260).

Author information

Authors and Affiliations

  1. Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA

    Yuanyue Zhang, En Xu, Kunal Singh, Derek B. Sant’Angelo & Qi Yang

  2. Department of Immunology & Microbial Disease, Albany Medical College, Albany, NY, USA

    Jacob T. Bailey, Shanti D’Souza & Wei Sun

  3. Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Marieke Lavaert & Avinash Bhandoola

  4. Metaorganism Immunity Section, Laboratory of Immune System Biology and Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA

    Verena M. Link & Yasmine Belkaid

  5. Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA

    Alex Hafiz & Jian Cao

  6. Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA

    Jian Cao

  7. Rutgers Institute for Translational Medicine and Science, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA

    Gaoyuan Cao & Qi Yang

  8. Department of Pediatrics, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA

    Derek B. Sant’Angelo & Qi Yang

  9. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA

    Yasmine Belkaid

  10. Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA

    Dorian B. McGavern

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Contributions

Y.Z., D.B.M. and Q.Y. conceived the ideas and designed the experiments. Y.Z. and Q.Y. performed the experiments, with the help of J.T.B., K.S., E.X., A.H., J.C., W.S., D.B.S.’A. and D.B.M. M.L. and A.B. provided Fig. 2b and Table 1. V.M.L. and Y.B. provided Fig. 2f,g,h. S.D.’S. developed and optimized in vitro MAIT cell culture methods for Fig. 3. Y.Z. and Q.Y. wrote the manuscript with the help of D.B.M. All authors reviewed, edited and approved the manuscript.

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Correspondence to Qi Yang.

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Nature Immunology thanks Robyn Klein, Paul Klenerman and Julie Siegenthaler for their contribution to the peer review of this work. L. A. Dempsey was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team. Peer reviewer reports are available.

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Extended data

Extended Data Fig. 1 Expression of transcription factors by meningeal MAIT cells.

Feature plots depicting expression for the indicated genes by scRNA-seq analysis with meningeal MAIT cells and CD4 and CD8 T cells in 7-month-old Mr1+/+ and Mr1−/− mice. Data are from 6 mice pooled per group.

Extended Data Fig. 2 Validation of adoptive transfer of MAIT cells.

a, Representative flow cytometry profiles depict gating strategies to sort donor MAIT cells for adoptive transfer experiments. Meningeal tissue was pooled, with tissue from 5 mice in 1 ml of Liberase digestion buffer. Digested tissue from up to 60 mice was pooled per sample, followed by staining with MR1 tetramers and surface antibodies to identify MAIT cells. Events of around 8% of the sample (equivalent to around 5 mice) were collected in the representative flow cytometry profiles. CD3 and TCRβ antibodies were not included for purification of MAIT cells for adoptive transfer. Donor MAIT cells were identified as CD45+ Thy1.2hiIL-18RhiMR1-tetramer+cells. b, Representative profiles of MAIT cells in the meninges of 7-month-old Mr1−/− mice that received adoptive transfer of PBS or MAIT cells. Plots were pre-gated on CD45+CD11b−B220−NK1.1- Thy1.2+ cells. c, Numbers of meningeal MAIT cells per mouse in the meninges and in the small intestinal laminal propria (SILP) of recipient mice at the indicated time points after adoptive transfer. d, Percentages of MAIT cells in the total T cell subset in the dura/arachnoid meningeal tissue obtained from inner calvaria and in the leptomeninges of recipient mice at 6 months post adoptive transfer. Error bars = Mean ± SE. Data are from 3 independent experiments, 2-5 recipient mice pooled in one sample for each experiment (b–d). Each data point indicates one independent experiment (c, d).

Source data

Extended Data Fig. 3 MAIT cells repress ROS accumulation and preserve expression of junctional molecules in dura/arachnoid meningeal tissue isolated from inner calvaria.

a, Representative profile of Reactive Oxygen Species (ROS) in the dura/arachnoid meningeal tissue obtained from the inner calvaria of 7-month-old Mr1+/+ and Mr1−/− mice with intra-cisterna magna administration of CellROX Green Reagent. b, Numbers of ROS positive cells in the meningeal tissue. c, Representative imaging profile of ROS in the dura/arachnoid meningeal tissue of 7-month-old Mr1−/− mice that received adoptive transfer of PBS or MAIT cells. d, Numbers of ROS + cells in the meningeal tissue in Mr1−/− mice that received adoptive transfer of PBS or MAIT cells. e, Representative imaging profile depicting expression of CD31 and E-cadherin in dura/arachnoid meningeal tissue in 7-month-old Mr1+/+ and Mr1−/− mice, with i.c.m. injection of fluorescence conjugated CD31 and E-cadherin antibodies. f, Fluorescence intensity of E-cadherin in the meninges of Mr1+/+ and Mr1−/− mice. g, Representative imaging profile depicting expression of CD31 and E-cadherin in dura/arachnoid meningeal tissue in 7-month-old Mr1−/− mice that received adoptive transfer of PBS or MAIT cells. h, Fluorescence intensity of E-cadherin in the meninges of Mr1−/− mice that received adoptive transfer of PBS or MAIT cells. i, Representative profile of ROS detection in meninges of Mr1−/− mice treated with Glutathione or PBS control. j, Numbers of ROS positive cells in 7-month-old Mr1−/− mice treated with Glutathione or PBS control. k, Representative imaging profile depicting expression of CD31 and E-cadherin in dura/arachnoid meningeal tissue in 7-month-old Mr1−/− mice treated with Glutathione or PBS control. l, Fluorescence intensity of E-cadherin in dura/arachnoid meningeal tissue in Mr1−/− mice treated with Glutathione or PBS control. Error bars = Mean ± SE. Data are from 6 mice per group, representative of 2 independent experiments. **P < 0.01 using two-sided Student’s t-test; exact P values are provided in the source data.

Source data

Extended Data Fig. 4 Mr1−/− mice do not exhibit significant defects in BBB integrity.

Na-fluorescein concentrations in the serum and brain of 7-month-old mice with intraperitoneal administration of Na-fluorescein. Error bars = Mean ± SE; Data are from 6 mice per group, 2 independent experiments. **P < 0.01, n.s = not statistically significant (P > 0.05) using two-sided ANOVA with Dunnett’s correction; exact P values are provided in the source data.

Source data

Extended Data Fig. 5 Myeloid cells and astrocytes in the hippocampus of Mr1−/− mice.

a, UMAP analysis for the entire population of live cells isolated from the hippocampus of 7-month-old Mr1+/+ and Mr1−/− mice. b, Representative flow cytometry profiles for monocytes and neutrophils in the hippocampus of 7-month-old Mr1+/+ and Mr1−/− mice. Lungs from wild-type mice were used as a positive control for gating monocytes and neutrophils. c, Numbers of monocytes and neutrophils in the hippocampus of 7-month-old Mr1+/+ and Mr1−/− mice. d, Representative profile of immunofluorescence staining of GFAP in the HP DG region of 7-month-old Mr1+/+ and Mr1−/− mice. e, Numbers of astrocytes (GFAP+ cells) in the HP DG regions. f, UMAP analysis of astrocytes in the hippocampus of 7-month-old Mr1+/+ and Mr1−/− mice. scRNA-seq was performed with FACS-sorted live cells in the hippocampus. Gating strategy to sort live cells for scRNA-seq is shown in Supplementary Fig. 2. UMAP profiles for total live cells in the hippocampus are provide in a. The data subset for microglia was created using the ‘subset’ function of Seurat. g, Feature plots depict expression of Il33 and Gfap in astrocytes. h, Genes highly expressed by each astrocyte subset. i. Proportions of each astrocyte subset in Mr1+/+ and Mr1−/− mice. j, Differentially expressed genes (DEG) in the total astrocyte population and in each astrocyte subset, between Mr1+/+ and Mr1−/− mice. k, Feature plots depict expression of Uba52 in astrocytes. Error bars = Mean ± SE. Data are from 6 mice per group, pooled from two independent experiments (b-e), or are from 6 mice pooled per group (a, f-k). *P < 0.05, **P < 0.01, n.s = not statistically significant (P > 0.05) using two-sided Student’s t-test (c, e), or two-sided Wilcoxon rank sum test (k); exact P values are provided in the source data (c, e) or Supplementary Table 11.

Source data

Extended Data Fig. 6 Behavior tests results of Mr1−/− mice and control wild-type mice.

a, Total distance travelled, and percentages of time spent in the central zone, the corner, and the peripheral zone in Open Field test, by 7-month-old Mr1+/+ and Mr1−/− mice. b, Percentages of time spent in the closed arm in Elevated Plus Maze test, by 7-month-old Mr1+/+ and Mr1−/− mice. c, Percentages of time spent in the novel arms in Y-maze test, by 7-month-old Mr1−/− mice that received adoptive transfer of control CD4/CD8 T cells or PBS control. d, Escape latency in the 4 day training period of Water Maze test, by 7-month-old Mr1−/− mice that received adoptive transfer of control CD4/CD8 T cells or PBS control. e, Entries to the target zone, latency to the target zone, and Percentage of time spent in the target quadrant, in day 5 probe trial of Water Maze Test, by 7-month-old Mr1−/− mice that received adoptive transfer of control CD4/CD8 T cells or PBS control. f, Fluorescence intensities of E-cadherin in the leptomeninges of 7-month-old Mr1−/− mice that received adoptive transfer of control CD4/CD8 T cells or PBS control. g, Fluorescence intensities of E-cadherin in the leptomeninges of 7-month-old Mr1−/− mice that received adoptive transfer of MAIT T cells or PBS control. h, Percentages of time spent in the novel (N) and familiar (F) arms in Y-maze test, by young 5−week-old Mr1+/+ and Mr1−/− mice. i, Escape latency in Water Maze 4-day training, by 5-week-old Mr1+/+ and Mr1−/− mice. Error bars = Mean ± SE. Data are from 9 mice per group (a–e) or 5 mice per group (f, g), or 10 mice per group (h, i), representative of 2 independent experiments. *P < 0.05, n.s = not statistically significant (P > 0.05) using two-sided Student’s t-test; exact P values are provided in the source data.

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Zhang, Y., Bailey, J.T., Xu, E. et al. Mucosal-associated invariant T cells restrict reactive oxidative damage and preserve meningeal barrier integrity and cognitive function. Nat Immunol 23, 1714–1725 (2022). https://doi.org/10.1038/s41590-022-01349-1

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