Pro-inflammatory T cells in the central nervous system (CNS) are causally associated with multiple demyelinating and neurodegenerative diseases1,2,3,4,5,6, but the pathways that control these responses remain unclear. Here we define a population of inflammatory group 3 innate lymphoid cells (ILC3s) that infiltrate the CNS in a mouse model of multiple sclerosis. These ILC3s are derived from the circulation, localize in proximity to infiltrating T cells in the CNS, function as antigen-presenting cells that restimulate myelin-specific T cells, and are increased in individuals with multiple sclerosis. Notably, antigen presentation by inflammatory ILC3s is required to promote T cell responses in the CNS and the development of multiple-sclerosis-like disease in mouse models. By contrast, conventional and tissue-resident ILC3s in the periphery do not appear to contribute to disease induction, but instead limit autoimmune T cell responses and prevent multiple-sclerosis-like disease when experimentally targeted to present myelin antigen. Collectively, our data define a population of inflammatory ILC3s that is essential for directly promoting T-cell-dependent neuroinflammation in the CNS and reveal the potential of harnessing peripheral tissue-resident ILC3s for the prevention of autoimmune disease.
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We thank members of the Sonnenberg laboratory for discussions and critical reading of the manuscript; the Microbiome Core and Epigenomics Core of Weill Cornell Medicine and G. G. Putzel for technical assistance; C. Gai of Weill Cornell’s Center of Comparative Medicine and Pathology (CCMP) for performing the parabiosis surgeries; and I. Ivanov of Columbia University for sharing mouse lines. The Sonnenberg laboratory is supported by the National Institutes of Health (R01AI143842, R01AI123368, R01AI145989, R01AI162936, R21CA249284 and U01AI095608), the National Institute of Allergy and Infectious Diseases (NIAID) Mucosal Immunology Studies Team (MIST), the Crohn’s and Colitis Foundation, the Searle Scholars Program, the American Asthma Foundation Scholar Award, Pilot Project Funding from the Center for Advanced Digestive Care (CADC), an Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund, a Wade F.B. Thompson–Cancer Research Institute (CRI) CLIP Investigator grant, the Meyer Cancer Center Collaborative Research Initiative, the Dalton Family Foundation, L. and G. Greenberg, and the Jill Roberts Institute for Research in Inflammatory Bowel Disease. G.F.S. is a CRI Lloyd J. Old STAR. J.B.G is supported by the NIAID of the National Institutes of Health under award number F31AI138389-01A1; A.M.J is supported by T32DK116970; and the Waisman laboratory is supported by the Deutsche Forschungsgemeinschaft (DFG) grants AW1600/10-1, AW1600/11-1 and AW1600/14-1, as well as by the National Multiple Sclerosis Society (NMSS) grant RG 1707-28780.
The authors declare no competing interests.
Peer review information Nature thanks the anonymous reviewers for their contribution to the peer review of this work.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Extended data figures and tables
a, Representative time course and clinical disease categorization of active EAE (n = 4, 5 mice/timepoint). b-c, Quantification of ILC3 frequency and absolute counts within indicated tissues at steady state (Naive) (n = 6 mice) versus EAE onset (d11, n = 7), acute (d15, n = 8) or chronic (d20, n = 9) phase (b) and reverse flow cytometry gating strategy defining all GFP+ cells in the CNS (d15) (n = 4 mice/group) (c) during EAE in Rorc-eGFP mice. d-e, Naive C57BL/6 mice (n = 4 mice/group) were immunized with either PBS (Naive), CFA/PTx alone, or with CFA/PTx/MOGp. At day 15 post-immunization, ILC3s in the CNS, inLN and cLN were enumerated by flow cytometry: d, Representative flow cytometry gating strategy for ILC3s in CNS (Lin1 = CD3, CD5, CD8, Lin2 = CD11b, CD11c, B220), e, Quantitation of frequencies and absolute counts of ILC3s. f-g, Representative flow cytometry on YFP+ ILCs (f) and quantification of differential expression of ILC heterogeneity in YFP+/- ILCs (g) in the CNS of Rorc-creeYFP mice during active EAE (n = 6 mice/group) (Lin 1 = B220, CD11b, CD11c, Lin 2 = CD3ε, CD5, CD8, Ly6C). Data in a-f are representative of two independent experiments with similar results and data in b are pooled from two independent experiments. Results are shown as mean ± s.d. Statistics are calculated by one-way (b, e) analysis of variance (ANOVA) with Sidak’s multiple comparisons test.
a-c, Heat maps showing absolute log normalized counts (one plus log 2) (a, b) or relative expression Z-scores (c) from RNA sequencing of indicated lineage-specifying genes in sorted ILC3s from the cLN, CNS, or small intestine lamina propria (SI-LP) of Rorc-eGFP mice during peak of active EAE (n = 4 mice). d, Quantification of cytokine production by ILC3s (CD45+, CD3ε-, CD5-, CD8α-, TCRγδ-, NK1.1-, CD11b-, CD11c-, B220-, CD127+, CD90.2+, KLRG1-, RORγt+) in indicated tissues during EAE (day 15) C57BL/6 mice (n = 4 mice). e, Representative flow cytometry gating strategy to detect ILC3s in human PBMCs (Lineage = CD19, CD94, CD14, CD123, FcR1a, CD11c) and frequency quantification of ILC3s in healthy control (HC) or RRMS samples (n = 18 sample-pairs – Supplementary Table 1). Data in d are representative of two independent experiments with similar results. Data in e are pooled and representative of two independent flow cytometry experiments on cryopreserved PBMC sample sets with similar results. Results are shown as mean ± s.d. Statistics are calculated by one-way analysis of variance (ANOVA) with Sidak’s multiple comparisons test (d).
Extended Data Fig. 3 Expression of MHCII and co-stimulatory molecules on ILC3s during neuroinflammation.
a, d, Representative histograms and quantification of MHCII (a), and CD80 or CD86 (d) expression on ILC3s in indicated tissues of Rorc-eGFP mice at steady state (Naive) (n = 3 mice) versus EAE onset (d11, n = 4), acute (d15, n = 4) or chronic (d20, n = 5) phase. b, Naive C57BL/6 mice were immunized with either PBS (Naive), CFA/PTx or with CFA/PTx/MOGp (n = 4 mice/group). At day 15 EAE, frequency and counts of MHCII+ ILC3s in the CNS and cLN were enumerated by flow cytometry. c, e Representative staining and quantification of HLA-DR (c) and co-stimulatory molecules (e) on human blood ILC3s (n = 18 samples/group). Data in a, b, d are representative of two independent experiments with similar results. Results are shown as mean ± s.d. Statistics are calculated by one-way (b) analysis of variance (ANOVA) with Sidak’s multiple comparisons test.
a-b, Naive C57BL/6 mice were immunized with either PBS (Naive), CFA/PTx or with CFA/PTx/MOGp (EAE) (n = 4 mice/group). At day 15 post immunization, expression of co-stimulatory molecules CD80, CD86 (a) and OX40L, CD40, and CD30L (b) by MHCII+ ILC3s in the mLN, inLN, cLN and CNS were enumerated by flow cytometry. Data are representative of three independent experiments with similar results. Results are shown as mean ± s.d.
Extended Data Fig. 5 ILC3s are found in the cerebral spinal fluid of patients with RRMS and express HLA-DR and CD86.
a, Validation of anti-RORγt antibody staining on single cell suspensions from human donor tonsils compared to FMO (Fluorescence Minus One) control indicating staining without anti-RORγt antibody. b-e, Cerebral spinal fluid (CSF) was obtained from 7 patients with RRMS and one control individual (other neurological disease, OND). Individuals were further stratified by the presence or absence of contrast enhancing lesions (CEL) as well as CEL number (Supplementary Table 2). CSF was processed immediately by centrifuging for 10 min at 400 x g and staining for ILC3s as indicated (b) (Lineage = CD19, CD94, CD14, CD123, FcR1a, CD11c). Gated RORγt+ populations in the indicated tissues exhibited dim staining for CD45, which is a defining feature of ILC3s, relative to CD4 T cells (c). Indicated frequencies of ILC3s in the CSF were quantified (d). PBMCs were used as controls during each collection and used for comparison of HLA-DR or CD86 expression on ILC3s in the CSF (e). Results are shown as mean (d) and RRMS flow cytometry is representative flow cytometry from CSF of patient #2 (Supplementary Table 2). Human tonsil data is representative of 3 individual tonsil samples.
a, Representative immunofluorescence staining of fixed dura meninges, brain cerebellum and spinal cord (edge denoted by dashed white line) from Rorc-eGFP mice during day 11 or day 18 of active EAE showing enrichment of GFP+ cells in focal lesions of the parenchyma (representative of n = 3 mice/timepoint). b-c, Frequency of cytokine producing 2D2 T cells after 72 h co-culture with ex vivo sorted cDC or alone (2D2 T cells alone) from the CNS (b) or the mLN (c) (pooled from 5 mice, d18 EAE) in the presence of MOGp +/- α-MHCII blocking antibody. d, To determine the ability to process full-length antigen 2D2 T cells and ILC3s were sorted from the CNS (pooled from n = 5 mice, d19 EAE) and co-cultured as indicated for 72 h prior to determination of cell counts, staining of IFNγ or CD25 for flow cytometry. Resulting 2D2 cell counts were measured and normalized as a fold-change in comparison to myelin-specific 2D2 T cells cultured alone (no APC) and treated with MOGp1-125 (dashed line) (left graph). Data in d are pooled from two independent experiments and data are representative of two (b-c) independent experiments with similar results. Data were necessarily pooled in noted experiments due to limited cell numbers. Results are shown as mean ± s.d. Statistics are calculated by one-way analysis of variance (ANOVA) with Sidak’s multiple comparisons test. Data points indicate technical well replicates and dashed lines (b-d) indicate baseline cytokine production by 2D2 T cells alone from indicated tissues.
a, Expression of MHCII was quantified by flow cytometry in indicated antigen-presenting cells from the cLN or CNS of indicated mice at steady state (n = 4 mice/group). b-c Representative flow cytometry gating strategy for indicated immune cell populations in the CNS (b) and expression of YFP in indicated cell populations and tissues (c) of Rorc-creeYFP mice at day 15 of active EAE. d, Reverse flow cytometry gating strategy defining all YFP+ fate-mapped cells in the CNS of Rorc-creeYFP mice (day 15 EAE) (Lin 1 = B220, CD11b, CD11c, Lin 2 = CD3ε, CD5, CD8, Ly6C). Results are shown as mean ± s.d. Statistics are calculated by one-way analysis of variance (ANOVA) with Sidak’s multiple comparisons test (a). Data in a-d are representative of two independent experiments with similar results
Extended Data Fig. 8 Effect of ILC3-specific MHCII and generalized intestinal inflammation on neuroinflammation.
a-d, Naive 2D2 T cells (Thy1.1+) were transferred into recipient mice, which were immunized 24 h later to induce active EAE. At day 14 EAE, frequencies and counts (a), activation/proliferation (b), and polarization (c) of donor Thy1.1+ 2D2 T cells (c, upper panel) or endogenous T cells (c, lower panel) were analysed by intracellular flow cytometry in the cLN or inLN (n = 9 mice/group (a, b), n = 5 mice/group (c)). d, Frequencies of IFNγ-producing endogenous T cells in the CNS were quantified by intracellular flow cytometry cytokine staining (n = 8 mice/group). e-f, Passive EAE was induced in recipient mice and day 15 frequencies of Thy1.1+ 2D2 T cells in the cLN and CNS were determined by flow cytometry (n = 4 mice/group) (e). Representative H&E of fixed transverse spinal cord sections of mice shown at 4X magnification (top, scale bar = 300 µM) with 20X inset magnification (bottom, scale bar = 75 µm) of cellular infiltration near ventromedial fissure at day 15 passive EAE (f). g-h, Average clinical scores in indicated mice (MHCIIΔTcell = CD4-cre+ x H2-Ab1fl/fl) after induction of active EAE (n = 4 mice/group (g), n = 5 mice/group (h)). i, C57BL/6 mice were treated with either 3% D.S.S. in the drinking water for 7 days or were orally gavaged with C. rodentium (n = 5 mice/group). Active EAE was induced 14 days later and clinical scores were taken on mice or controls. Data are representative of two (g-i) or three (a-f) independent experiments with similar results. Data are pooled from two independent experiments in a, b, d. Results are shown as mean ± s.d. (a-e) or s.e.m (g-i) Statistics are calculated by two-way analysis of variance (ANOVA) (c, d) with Sidak’s multiple comparisons test or unpaired, two-tailed t-test (Mann–Whitney U-test) (a, b, e).
a-d, Littermate H2-Ab1fl/fl and MHCIIΔILC3 mice were treated with Vancomycin (Vanco) in the drinking water for 7 days prior to induction of active EAE and Vanco was continued throughout EAE. a, PCoA (Weighted UniFrac) of 16S rRNA gene sequencing of faecal samples at indicated treatment timepoints (n = 5 mice/group, rep. of N = 2). At the end of EAE plus vancomycin treatment, b, colon lengths, spleen mass, c, and total frequencies of endogenous neutrophils, CD4 T cells, and transferred Thy1.1+ 2D2 T cells in the indicated gastro-intestinal tissues. LI-LP = large intestine lamina propria. d, Daily (n = 5 mice/group) and cumulative clinical scores of mice (n = 9 mice/group, pooled from N = 2). e-f, Splenic antigen-presenting cells (APCs: DCs or B cells) were sort-purified from steady state (e) or CFA-treated mice (f, d10) and co-cultured with 2D2 T cells previously stained with violet cell trace violet. Groups included 2D2 T cells alone (no APC), 2D2 T cells plus APC, or 2D2 T cells plus APC and MOG peptide. After 72 h, proliferation of 2D2 T cells was determined by flow cytometry to measure cell trace violet dilution from cell division. g, Average clinical scores in indicated mice after induction of active EAE (n = 18-21 mice/group left panel pooled from three independent experiments with similar results, n = 13-4 mice/group middle panel pooled from three independent experiments with similar results, right panel n = 3 mice/group representative of two independent experiments with similar results). Results are shown as mean ± s.e.m (d left panel, g) or mean ± s.d. (a-c, d right panel). Statistics are calculated by two-tailed t-test (Mann–Whitney U-test) (b, d) or two-way analysis of variance (ANOVA) (c) with Sidak’s multiple comparisons test. Results in a are representative of two independent experiments (n = 4-5 mice/group) and data in b-d are pooled from N = 2.
Extended Data Fig. 10 Antigen presenting group 3 innate lymphoid cells orchestrate neuroinflammation.
a, ILC3 family heterogeneity with inflammatory ILC3s (iILC3s) depicted in yellow. b, During autoimmune neuroinflammation, iILC3s enter the CNS from the circulation and are essential to promote pro-inflammatory T cell responses and demyelinating disease through antigen presentation. c, Tissue-resident and peripheral ILC3s retain tolerogenic potential, and when targeted to express myelin peptide can eliminate self-specific T cells and prevent demyelinating disease.
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Grigg, J.B., Shanmugavadivu, A., Regen, T. et al. Antigen-presenting innate lymphoid cells orchestrate neuroinflammation. Nature 600, 707–712 (2021). https://doi.org/10.1038/s41586-021-04136-4
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