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Gradients of the signaling lipid S1P in lymph nodes position natural killer cells and regulate their interferon-γ response

Nature Immunology volume 18, pages 15–25 (2017)Cite this article

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Abstract

The lymph node periphery is an important site for many immunological functions, from pathogen containment to the differentiation of helper T cells, yet the cues that position cells in this region are largely undefined. Here, through the use of a reporter for the signaling lipid S1P (sphingosine 1-phosphate), we found that cells sensed higher concentrations of S1P in the medullary cords than in the T cell zone and that the S1P transporter SPNS2 on lymphatic endothelial cells generated this gradient. Natural killer (NK) cells are located at the periphery of the lymph node, predominantly in the medulla, and we found that expression of SPNS2, expression of the S1P receptor S1PR5 on NK cells, and expression of the chemokine receptor CXCR4 were all required for NK cell localization during homeostasis and rapid production of interferon-γ by NK cells after challenge. Our findings elucidate the spatial cues for NK cell organization and reveal a previously unknown role for S1P in positioning cells within the medulla.

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Figure 1: Cells in the medullary cords sense higher concentrations of extracellular S1P than do cells in the T cell zone.
Figure 2: NK cells are displaced into the T cell zone of LN in Spns2ΔLyve1 mice.
Figure 3: Mislocalization causes defective IFN-γ production by LN NK cells in Spns2ΔLyve1 mice after infection.
Figure 4: NK cells are displaced into the T cell zone of LNs in S1pr5−/− mice.
Figure 5: Mislocalization causes defective IFN-γ production by S1pr5−/− LN NK cells after infection.
Figure 6: NK cells are displaced into the T cell zone of LNs after antagonism of CXCR4.
Figure 7: Mislocalization causes defective IFN-γ production by LN NK cells after infection in mice treated with an antagonist of CXCR4.

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Acknowledgements

We thank members of the Schwab laboratory for discussions; K. Cadwell (New York University School of Medicine) for Salmonella enterica Typhimurium; M. Bigaud and V. Brinkmann (Novartis) for NIBR-0213; K. Manova, S. Fujisawa, and Y. Romin for assistance with microscopy and image analysis; and B. Breart and J. Cyster for critical reading of the manuscript. Supported by the US National Institutes of Health (R01 AI085166 to S.R.S.; T32 AI100853 to V.F. and A.M.; and R01 DA019674 and NS084398 to J.C.).

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  1. Willy D Ramos-Perez

    Present address: Present address: Microbiology and Medical Zoology Department, University of Puerto Rico School of Medicine, San Juan Puerto Rico, USA.,

Authors and Affiliations

  1. Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York, USA

    Victoria Fang, V Sai Chaluvadi, Willy D Ramos-Perez, Alejandra Mendoza, Audrey Baeyens & Susan R Schwab

  2. Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California, USA

    Richard Rivera & Jerold Chun

  3. Microscopy Core, Office of Collaborative Science, New York University Langone Medical Center, New York, New York, USA

    Michael Cammer

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Contributions

V.F. designed and conducted experiments, wrote ImageJ software programs, analyzed data and wrote the manuscript; V.S.C. conducted experiments and analyzed data; W.D.R.-P., A.M., and A.B. conducted experiments; R.R. and J.C. provided S1pr5−/− mice; M.C. wrote ImageJ software programs; and S.R.S. designed experiments, interpreted data and wrote the manuscript.

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Correspondence to Susan R Schwab.

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Integrated supplementary information

Supplementary Figure 1 Analysis of LN S1P gradients.

(a) Diagram showing the spatial distribution of NK cells in WT LN. Inset: Upon infection, sinus-lining macrophages secrete IL-18 and other cytokines, which stimulate IFN-γ production by NK cells. IFN-γ in turn activates microbicidal activity in the macrophages.

(b) Diagram showing the response to S1P by cells expressing the reporter construct.

(c) FTY720 treatment demonstrates that reporting macrophages within the medulla are not saturated with S1P. S1P reporter mice (Mx1-Cre) were treated i.p. with 1 mg/kg of the S1PR1 agonist FTY720 or vehicle 5h before LN harvest. LN sections were stained with antibodies against GFP (green), RFP (red), CD11b (white), Lyve1 (not shown) and B220 (not shown). Left: Representative cells from the medullary cords and medullary sinuses of FTY720-treated and vehicle-treated S1P reporter mice. Scale bar, 5 μm. Representative of 2 pairs of mice analyzed in 2 experiments (image file: https://figshare.com/s/2918068753bfab0d44d9). Right: Quantification of the GFP:RFP ratio on the surface of reporting cells as in Fig. 1c. Each point on the graph represents the average ratio over an area of at least 7x102 square microns. Horizontal lines indicate the mean and SEM. Ratios were not normalized. Graph shows data from 1 pair of mice, representative of 2 experiments. *, p<0.01; **, p<0.0001 (Fisher’s LSD test).

(d) Reporter-transduced T cells sense more S1P in the medullary cords than the T zone. T cells isolated from WT CD45.1+ or Cd69−/− CD45.1+ mice were retrovirally transduced with the S1P reporter and intravenously transferred to WT CD45.2+ mice. LN were harvested for sectioning and confocal imaging 1d after transfer. We used Cd69−/− T cells to avoid CD69-mediated S1PR1 internalization, although we did not see any differences between reporting by Cd69−/− and WT T cells (not shown)27. Left: LN sections were stained with antibodies against GFP (green), RFP (red), CD45.1 (to identify the surface of transferred cells, not shown), Lyve1 (not shown), and B220 (not shown). Representative cells are shown from the T zone and medullary cords. Scale bars, 5 μm (image files: https://figshare.com/s/6f5313a7d5141469304e). Right: Quantification of S1P reporting by transferred T cells in the T zone and medullary cords. The ratio of GFP to RFP for each CD45.1+RFP+ pixel was calculated, and the ratio was averaged over individual cells. Graph compiles 19 cells in the medullary cords and 55 cells in the T zone from 16 sections (14 from 2 mice with Cd69−/− donor T cells analyzed in 2 experiments, and 2 from 1 mouse with WT donor T cells in 1 experiment). Center line represents the median, box limits extend from the 25th to 75th percentile, Tukey whiskers extend to 1.5 × IQR beyond the box, and symbols represent outliers. For each experiment all ratios were normalized such that the average ratio for the T zone was 1.0. *, p<0.01 (unpaired Student’s 2-tailed t-test). (Supplementary Note 2)

Supplementary Figure 2 Identification of NK cells in tissue sections.

Most NK1.1+ cells in LN sections are NKp46+ NK cells. Confocal immunofluorescence image of a LN section from a WT animal stained with anti-NK1.1 (green), anti-NKp46 (magenta), and anti-Lyve1 (blue). Image is representative of 2 mice in 2 experiments. Scale bars, 20 μm. More than 85% of NK1.1+ cells are also positive for NKp46. In most experiments, we identified NK cells by expression of NK1.1 rather than the more NK-specific NKp46 because the anti-NK1.1 antibody was more robust in our hands. Because the vast majority of cells that stain with NK1.1 in LN sections are NKp46+, potential mislocalization of NKT cells or other NK1.1+ subsets would not substantially affect the results.

Supplementary Figure 3 NK cell defects are not accompanied by gross mislocalization of CD169+ macrophages.

In WT mice, CD169+ macrophages line the SCS and medullary sinuses. Representative images of LN from the indicated animals showing localization of macrophages. B cells were stained with anti-B220, LEC and some sinus-lining macrophages with anti-Lyve1, and a subset of macrophages with anti-CD169. Scale bars, 100 μm.

(a) LN sections from a Spns2ΔLyve1 mouse (bottom) and littermate control (top). Representative of 2 pairs of mice in 2 experiments.

(b) LN sections from an S1pr5−/− mouse (bottom) and littermate control (top). Representative of 2 pairs of mice in 2 experiments.

(c) LN sections from an AMD3100-treated mouse (bottom) and PBS-treated control (top). B cells (B220) and LEC (Lyve1) were stained with the same fluorophore but can be distinguished by morphology. Representative of 2 pairs of mice in 2 experiments.

(d) LN sections from a Cxcr4ΔMx 1 mouse (bottom) and littermate control (top). Representative of 2 pairs of mice in 2 experiments.

Supplementary Figure 4 Cell-intrinsic requirement for S1PR5 in NK cell localization.

NK cell frequency in LN of Spns2 ΔLyve1 mice. NK cell frequency (left) and absolute number (right) in peripheral LN (2 inguinal, 2 axillary, 2 brachial) of Spns2ΔLyve1 mice and littermate controls. As previously reported26, 44, SPNS2-deficient mice have small LN compared to controls. Lines indicate the mean. Graphs compile 6 pairs of mice analyzed in 3 experiments. *, p<0.05 (unpaired Student’s 2-tailed t-test).

NK cell frequency in LN of S1pr5−/− mice. NK cell frequency (left) and absolute number (right) in peripheral LN (2 inguinal, 2 axillary, 2 brachial) of S1pr5−/− mice and littermate controls. Lines indicate the mean. Graphs compile 6 (left) or 5 (right) pairs of mice analyzed in 4 (left) or 3 (right) experiments. *, p<0.05 (paired Student’s 2-tailed t-test).

Original images for Fig. 4f. LN sections were stained with antibodies against NK1.1 (magenta), Lyve1 (blue), and B220 (blue) (although they were both stained with BV421-conjugated antibodies, Lyve1+ LEC and macrophages and B220+ B cells can be readily distinguished by morphology). Note: the occasional cells expressing very bright GFP did not co-stain with NK1.1. Scale bars, 200 μm. Insets: Green arrows indicate GFP+ NK cells. White arrows indicate GFP- NK cells. Single channel images of GFP are shown at the bottom. Scale bars, 20 μm.

Supplementary Figure 5 NK cell localization during infection.

NK cell frequency in LN of AMD3100-treated mice. NK cell frequency (left) and absolute number (right) in peripheral LN (2 inguinal, 2 axillary, 2 brachial) of AMD3100- or PBS-treated mice. LN were harvested 2h after treatment. Lines indicate the mean. Graphs compile 6 pairs of mice analyzed in 2 experiments.

A subset of LN NK cells expresses CXCR3 during homeostasis. Surface CXCR3 staining on LN NK cells (NK1.1+CD3−) and CD4+ T cells in a representative Spns2ΔLyve1 mouse and littermate control. Representative of 4 pairs of mice in 2 experiments.

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Fang, V., Chaluvadi, V., Ramos-Perez, W. et al. Gradients of the signaling lipid S1P in lymph nodes position natural killer cells and regulate their interferon-γ response. Nat Immunol 18, 15–25 (2017). https://doi.org/10.1038/ni.3619

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