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Neutrophils license iNKT cells to regulate self-reactive mouse B cell responses

Nature Immunology volume 17, pages 1407–1414 (2016)Cite this article

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Abstract

The innate responsiveness of the immune system is important not only for quick responses to pathogens but also for the initiation and shaping of the subsequent adaptive immune response. Activation via the cytokine IL-18, a product of inflammasomes, gives rise to a rapid response that includes the production of self-reactive antibodies. As increased concentrations of this cytokine are found in inflammatory diseases, we investigated the origin of the B cell response and its regulation. We identified an accumulation of B cell–helper neutrophils in the spleen that interacted with innate-type invariant natural killer T cells (iNKT cells) to regulate B cell responses. We found that neutrophil-dependent expression of the death-receptor ligand FasL by iNKT cells was needed to restrict autoantibody production. Neutrophils can thus license iNKT cells to regulate potentially harmful autoreactive B cell responses during inflammasome-driven inflammation.

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Figure 1: Accumulation and activation of neutrophils in inflammation.
Figure 2: IL-18 induces BAFF expression by neutrophils, which supports B cell viability.
Figure 3: IL-18 activates neutrophils to enable interaction with iNKT cells.
Figure 4: The activation of neutrophils depends on cognate interactions with iNKT cells.
Figure 5: The activation of iNKT cells by IL-18 and phenotypic licensing by neutrophils.
Figure 6: FasL expression by iNKT cells is needed to limit autoreactive B cell responses.
Figure 7: The restriction of autoreactive B cells by iNKT cells requires cognate interactions and is defective without licensing by neutrophils.

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Acknowledgements

We thank M. Tighe, A. Duhlin, E. Lind and P. Lanthier for technical assistance; M. Winerdal for illustrations; the US National Institutes of Health tetramer core facility for CD1d tetramers; M. Johansson and P. Höglund (Karolinska Institutet) for iNKT cell–deficient C57BL/6 Cd1d1−/− mice and C57BL/6 Traj18−/− mice backcrossed for more than ten generations; and S. Smiley (Trudeau Institute) for Pad4−/− mice on a BALB/c background. Supported by the Swedish Research Council, The Center for Allergy Research Karolinska Institutet, The Swedish Medical Society, King Gustaf V's 80-year Foundation, the Magnus Bergvall Foundation, the Karolinska Institutet (M.C.I.K.), the Erik and Edith Fernström foundation, the Swedish Society for Medical Research, the Centre for Allergy Research, the Ellen, Walter and Lennart Hesselman foundation (T.H.), O.E. and Edla Johansson's Foundation, Tore Nilsson's foundation, Karolinska Institutet's foundations (S.K.S.), the US National Institutes of Health (AI104788-01A1 to E.A.L.), the Trudeau Institute and the University of Texas Health Science Center at San Antonio (E.A.L.).

Author information

Author notes

  1. Elizabeth A Leadbetter and Mikael C I Karlsson: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solna, Sweden

    Thomas Hägglöf, Saikiran K Sedimbi & Mikael C I Karlsson

  2. Trudeau Institute, Saranac Lake, New York, USA

    Jennifer L Yates & Elizabeth A Leadbetter

  3. Department of Clinical Neuroscience, Karolinska Institutet, Centre for Molecular Medicine, Karolinska University Hospital at Solna, Solna, Sweden

    Roham Parsa & Robert A Harris

  4. Department of Microbiology, Immunology, and Molecular Genetics, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA

    Briana Hauff Salas & Elizabeth A Leadbetter

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Contributions

T.H., S.K.S., R.P., E.A.L. and M.C.I.K. designed experiments; T.H., S.K.S., J.L.Y., R.P. and B.H.S. performed experiments; T.H., S.K.S., E.A.L., R.P., B.H.S. and M.C.I.K. analyzed and interpreted the data; T.H., E.A.L. and M.C.I.K. wrote the manuscript; and T.H., S.K.S., J.L.Y., R.P., B.H.S., R.A.H., E.A.L. and M.C.I.K. edited the manuscript.

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Correspondence to Mikael C I Karlsson.

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Integrated supplementary information

Supplementary Figure 1 Leukocyte expression of IL-18R, BAFF and Fas, plus evaluation of Pad4–/– mice.

(a) Flow cytometry detection of IL-18R on mouse naïve splenic neutrophils and follicular B cells. (b) Quantitative RT-PCR analysis of mRNA encoding BAFF (Tnfsf13b) in sorted splenic macrophages freshly isolated from vehicle or IL-18 injected mice at day 12. Results are normalized to mRNA encoding Hprt1 to determine mean fold change, and are presented as relative expression (RE) compared with splenic macrophages after vehicle treatment. (c) Flow cytometry of neutrophils cultured 16 h in vitro with medium (left panels) or 20 ng/ml IL-18 (right panels). Neutrophils were labeled with isotype control (top panels) or anti-BAFF antibody (clone 121808; bottom panels). Boxes indicate BAFF+ neutrophils. (d) Flow cytometry of frequency of CD11b+ Ly6G—macrophages (MØ) expressing surface BAFF following 16 h in vitro culture in the presence of 20 ng/ml IL-18 or medium. (e) Flow cytometry determination of frequencies of splenic B220+ B cells expressing Fas following co-culture with or without neutrophils and 20 ng/ml IL-18 or medium for 6 h, as noted. Anti-BAFF antibody or BAFF–R–Ig was added to the cultures to block BAFF. (f) Confocal immunofluorescence of neutrophil elastase in the spleens of wild-type (C57BL/6) mice treated with vehicle (left) or IL-18 (right) at day 12. (n = 3 per group). Scale bar, 100 μm. (g) ELISA measure of serum titers of total IgE and (h) anti-DNA IgM, IgG, and IgE antibodies (day 12) in homozygous Pad4–/– mice and heterozygous littermate controls on day 12 after injections with IL-18 or vehicle. *P < 0.05 [two-tailed unpaired Student’s t-test (b; n = 4 per group, 3 technical replicates), (d, n= 6 per group, 3 technical replicates), 2way ANOVA with Sidak correction (e, n= 5 per group, two technical replicates) or (g, h; n = 5 per group). Data are representative of one (f), two (e), three (c) experiments or pooled from two (d) or five experiments (g, h). Box height indicates mean + s.e.m.

Supplementary Figure 2 Mouse leukocyte CD1d expression and gating strategy for CD1d–/– mixed-BM chimeras.

(a) Flow cytometry plots of Ly6G+ CD11b+ neutrophils (upper left panel) and B220+ CD21+ CD23lo MZ B cells (upper right panel). CD1d expression of gated populations is displayed in corresponding lower panels. Black line represents WT (C57BL/6) mice, filled histogram represents CD1d–/– mice. (b) CD1d expression by CD8+ T cells (left panel) and CD11b+ Ly6G- macrophages (right panel) following 16 h in vitro stimulation with IL-18 (blue line) or vehicle (filled histogram). (c) Confocal immunofluorescence of day 12 IL-18 treated WT (C57BL/6) spleen stained for B220 (white), Ly6G (red), CD1d (blue), and CXCR6-GFP (green) reported. Boxed inset is magnified and displayed in right panel, the arrow indicates a neutrophil and iNKT cell in close proximity. Scale bar, 100 μm. (d) Flow cytometry gating strategy to identify CD1d–/– or WT neutrophils using congenic markers. Numbers in upper left panel indicate frequency of congenic populations. Gate in upper right panel identifies neutrophils. Expression of CD1d for WT (CD45.1+; lower left panel) and CD1d–/– (CD45.1-, lower right panel) neutrophils. Neutrophils from vehicle-injected controls in filled histograms and from IL-18-injected mice in colored histograms.

Supplementary Figure 3 iNKT cell and T cell phenotypes, plus leukocyte repopulation following neutrophil depletion during inflammation.

(a) Flow cytometry measure of percentage of CD69+ CD1d-tet+ iNKT cells (left panel) and MFI level on CD1d-tet+ iNKT cells (right panel) 4 and 12 hrs after IL-18 or vehicle administration to wild type (C57BL/6) mice in vivo. (b) Frequency of splenic γδT cells in vehicle or IL-18 injected mice at day 12 as assessed by flow cytometry. (c) Flow cytometry plots displaying representative neutrophil populations in mouse spleen (top panels) or blood (bottom panels) on day 12 following treatments indicated. Depletion antibody (anti-Ly6G- clone 1A8) administered on days 0 and 4. (d) Summary of flow cytometry data shown in (c), displaying kinetics of neutrophil numbers in spleen (upper panel) and blood (lower panel) in mice depleted at days 0 and 4. (e) Flow cytometry determination of number of splenic iNKT cells following treatment as indicated (depletion as in c). (f) ELISA measure of serum BAFF in mice treated as indicated. Data expressed as % of BAFF detected in vehicle treated mice. (g) Cytometric bead array kinetic measure of serum concentrations of IFN–γ from IL-18 or vehicle treated wild-type (C57BL/6) mice in the presence or absence of neutrophil depleting antibody (1A8) given days 0 and 4. (h) Intracellular flow cytometry data displaying MFI values for T-bet expression by iNKT cells in vehicle or IL-18 injected mice on day 12. (i) Intracellular flow cytometry data displaying MFI values for CD4+ and CD8+ T cell expression of the nuclear transcription factor GATA3 on day 12 after injection with IL-18 or vehicle. (j) Flow cytometry measure of FasL expression for conventional CD1d-tet– T cells after IL-18 injection, normalized to levels in cells from vehicle treated mice. *P < 0.05 (two-tailed unpaired Student’s t-test [(a, n = 3 per group), (b, d; n = 4 per group), (e; n = 8 mice per group), (h; n = 5 mice per group), (i; n = 5 mice per group), (j; 14 mice per group)] or [1way ANOVA with Tukey correction (f; n = 8 per group), (g; n = 5 per group)]. Data are representative of one (a, g), two (h, i), or pooled from two (b, e, j), three (f), or four experiments (d). Box height or symbol center indicates group mean + s.e.m.

Supplementary Figure 4 Characterization of iNKT cell–specific Fasl–/– chimeras.

(a) Flow cytometry data showing congenic marker expression (CD45.1+ vs CD45.2+) of cells from mixed BM chimeras generated by transfer of Traj18–/– + wild-type or Traj18–/– + Fasl–/– BM into Traj18–/– recipients. (b) Flow cytometry data showing gating strategy for iNKT cells in spleens of mixed BM chimeras discussed in (a). Congenic markers are used to identify lymphocytes derived from Traj18–/– (CD45.1+; left panels) vs wild-type or Fasl–/– (CD45.2+; right panels) BM within the same mouse. (c) Flow cytometry histograms showing expression of FasL in iNKT cells (top) and CD8+ T cells (bottom), gated as in (b). Filled histograms indicate expression in Fasl–/– cells; red histograms indicate expression in wild-type cells. (d) Flow cytometry data showing proportions of iNKT cells in chimeric mice reconstituted with wild-type [iNKT(WT FasL)] or Fasl–/– iNKT cells [iNKT(ΔFasL)]. *P < 0.05 (two-tailed unpaired Student’s t-test [(d; n = 4 per group). Data represents three independent experiments (a-d). Box height indicates group mean + s.e.m.

Supplementary Figure 5 Activation-marker expression by mouse B cell subsets and leukocyte characterization after continuous neutrophil depletion during IL-18-induced inflammation.

(a) Flow cytometry data showing frequencies of B cell subsets in wild-type (C57BL/6) compared to CD1d1–/– mice following injections with vehicle or IL-18, day 12. (b) ELISA measures of serum amounts of total IgM (left panel) and IgG (right panel) in WT and CD1d1–/– mice injected with vehicle or IL-18, day 12. (c-e) Flow cytometric analysis of activation marker expression by indicated B cell subset in the spleens of wild-type (C57BL/6) or CD1d1–/– mice following treatment with vehicle or IL-18, day 12. (f) Representative flow cytometry plots of splenic neutrophils on day 12 following vehicle or IL-18 treatment in combination with doubled neutrophil depletion strategy (Depl) using 500 μg of 1A8 antibody 24 h before IL-18 and on days 3, 6, and 9 in wild-type (C57BL/6) mice. Numbers below outlined areas indicate percent Ly6G+ CD11b+ neutrophils. (g) Summary of flow cytometry assessment of frequency of splenic Ly6G+ CD11b+ neutrophils from (g). (h) Left panel: Flow cytometry assessment of frequency of splenic CD138+ B220lo PCs day 12 after vehicle or IL-18 treatment in combination with neutrophil depletion according to (f). Center panel: Flow cytometry assessment of frequency of splenic B220+ CD95+ GL7+ GC B cells day 12 after vehicle or IL-18 treatment in combination with neutrophil depletion according to (f). Right panel: ELISA measure of serum concentrations of anti-DNA IgG antibodies in mice day 12 after vehicle or IL-18 treatment in combination with neutrophil depletion according to (f). (i) Intracellular flow cytometry assessment of expression in iNKT cells of the nuclear transcription factor GATA3 day 12 after vehicle or IL-18 treatment in combination with neutrophil depletion according to (f). *P < 0.05 (two-tailed unpaired Student’s t-test; wild-type (C57BL/6) IL-18 vs CD1d1–/– IL18 groups) (a-e; n = 5 mice per group) or (1way ANOVA with Tukey correction) (g-i; n = 4 per group). Data pooled from two experiments (a-e) or from one experiment (f-i). Box height indicates group mean + s.e.m.

Supplementary Figure 6 Autoreactive B cells are regulated by neutrophil-licensed iNKT cells during inflammation.

Neutrophil-dependent FasL expression by iNKT cells is required to restrict autoantibody production. Neutrophils can thus license iNKT cells to regulate potentially harmful autoreactive B cell responses during inflammasome-driven inflammation.

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Hägglöf, T., Sedimbi, S., Yates, J. et al. Neutrophils license iNKT cells to regulate self-reactive mouse B cell responses. Nat Immunol 17, 1407–1414 (2016). https://doi.org/10.1038/ni.3583

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