Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Subcapsular sinus macrophages prevent CNS invasion on peripheral infection with a neurotropic virus


Lymph nodes (LNs) capture microorganisms that breach the body’s external barriers and enter draining lymphatics, limiting the systemic spread of pathogens1. Recent work has shown that CD11b+CD169+ macrophages, which populate the subcapsular sinus (SCS) of LNs, are critical for the clearance of viruses from the lymph and for initiating antiviral humoral immune responses2,3,4. Here we show, using vesicular stomatitis virus (VSV), a relative of rabies virus transmitted by insect bites, that SCS macrophages perform a third vital function: they prevent lymph-borne neurotropic viruses from infecting the central nervous system (CNS). On local depletion of LN macrophages, about 60% of mice developed ascending paralysis and died 7–10 days after subcutaneous infection with a small dose of VSV, whereas macrophage-sufficient animals remained asymptomatic and cleared the virus. VSV gained access to the nervous system through peripheral nerves in macrophage-depleted LNs. In contrast, within macrophage-sufficient LNs VSV replicated preferentially in SCS macrophages but not in adjacent nerves. Removal of SCS macrophages did not compromise adaptive immune responses against VSV, but decreased type I interferon (IFN-I) production within infected LNs. VSV-infected macrophages recruited IFN-I-producing plasmacytoid dendritic cells to the SCS and in addition were a major source of IFN-I themselves. Experiments in bone marrow chimaeric mice revealed that IFN-I must act on both haematopoietic and stromal compartments, including the intranodal nerves, to prevent lethal infection with VSV. These results identify SCS macrophages as crucial gatekeepers to the CNS that prevent fatal viral invasion of the nervous system on peripheral infection.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Lymph node macrophages confer resistance to fatal invasion of the CNS on peripheral low-dose infection with VSV.
Figure 2: SCS macrophages are the primary targets for lymph-borne VSV and prevent infection of adjacent nerves.
Figure 3: Regulation of VSV-induced IFN-I production by SCS macrophages.


  1. 1

    von Andrian, U. H. & Mempel, T. R. Homing and cellular traffic in lymph nodes. Nature Rev. Immunol. 3, 867–878 (2003)

    CAS  Article  Google Scholar 

  2. 2

    Junt, T. et al. Subcapsular sinus macrophages in lymph nodes clear lymph-borne viruses and present them to antiviral B cells. Nature 450, 110–114 (2007)

    ADS  CAS  Article  Google Scholar 

  3. 3

    Phan, T. G., Grigorova, I., Okada, T. & Cyster, J. G. Subcapsular encounter and complement-dependent transport of immune complexes by lymph node B cells. Nature Immunol. 8, 992–1000 (2007)

    CAS  Article  Google Scholar 

  4. 4

    Carrasco, Y. R. & Batista, F. D. B cells acquire particulate antigen in a macrophage-rich area at the boundary between the follicle and the subcapsular sinus of the lymph node. Immunity 27, 160–171 (2007)

    CAS  Article  Google Scholar 

  5. 5

    Lyles, D. S. & Rupprecht, C. E. in Fields Virology 5th edn, Vol. 1 (ed. Howley, P. M & Knipe, D. M.) 1363–1408 (Lippincott Williams & Wilkins, 2007)

    Google Scholar 

  6. 6

    Hangartner, L., Zinkernagel, R. M. & Hengartner, H. Antiviral antibody responses: the two extremes of a wide spectrum. Nature Rev. Immunol. 6, 231–243 (2006)

    CAS  Article  Google Scholar 

  7. 7

    Probst, H. C. et al. Histological analysis of CD11c-DTR/GFP mice after in vivo depletion of dendritic cells. Clin. Exp. Immunol. 141, 398–404 (2005)

    CAS  Article  Google Scholar 

  8. 8

    Purtha, W. E., Chachu, K. A., Virgin, H. W. & Diamond, M. S. Early B-cell activation after West Nile virus infection requires α/β interferon but not antigen receptor signaling. J. Virol. 82, 10964–10974 (2008)

    CAS  Article  Google Scholar 

  9. 9

    Muller, U. et al. Functional role of type I and type II interferons in antiviral defense. Science 264, 1918–1921 (1994)

    ADS  CAS  Article  Google Scholar 

  10. 10

    Delemarre, F. G., Kors, N., Kraal, G. & van Rooijen, N. Repopulation of macrophages in popliteal lymph nodes of mice after liposome-mediated depletion. J. Leukoc. Biol. 47, 251–257 (1990)

    CAS  Article  Google Scholar 

  11. 11

    Chandran, K., Sullivan, N. J., Felbor, U., Whelan, S. P. & Cunningham, J. M. Endosomal proteolysis of the Ebola virus glycoprotein is necessary for infection. Science 308, 1643–1645 (2005)

    ADS  CAS  Article  Google Scholar 

  12. 12

    Hickman, H. D. et al. Direct priming of antiviral CD8+ T cells in the peripheral interfollicular region of lymph nodes. Nature Immunol. 9, 155–165 (2008)

    CAS  Article  Google Scholar 

  13. 13

    Brundler, M. A. et al. Immunity to viruses in B cell-deficient mice: influence of antibodies on virus persistence and on T cell memory. Eur. J. Immunol. 26, 2257–2262 (1996)

    CAS  Article  Google Scholar 

  14. 14

    Thomsen, A. R. et al. Cooperation of B cells and T cells is required for survival of mice infected with vesicular stomatitis virus. Int. Immunol. 9, 1757–1766 (1997)

    CAS  Article  Google Scholar 

  15. 15

    Asselin-Paturel, C. et al. Mouse type I IFN-producing cells are immature APCs with plasmacytoid morphology. Nature Immunol. 2, 1144–1150 (2001)

    CAS  Article  Google Scholar 

  16. 16

    Lund, J. M. et al. Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc. Natl Acad. Sci. USA 101, 5598–5603 (2004)

    ADS  CAS  Article  Google Scholar 

  17. 17

    Iparraguirre, A. et al. Two distinct activation states of plasmacytoid dendritic cells induced by influenza virus and CpG 1826 oligonucleotide. J. Leukoc. Biol. 83, 610–620 (2008)

    CAS  Article  Google Scholar 

  18. 18

    Detje, C. N. et al. Local type I IFN receptor signaling protects against virus spread within the central nervous system. J. Immunol. 182, 2297–2304 (2009)

    CAS  Article  Google Scholar 

  19. 19

    Jung, S. et al. In vivo depletion of CD11c+ dendritic cells abrogates priming of CD8+ T cells by exogenous cell-associated antigens. Immunity 17, 211–220 (2002)

    CAS  Article  Google Scholar 

  20. 20

    Maloy, K. J. et al. Qualitative and quantitative requirements for CD4+ T cell-mediated antiviral protection. J. Immunol. 162, 2867–2874 (1999)

    CAS  PubMed  Google Scholar 

  21. 21

    Mempel, T. R. et al. Regulatory T cells reversibly suppress cytotoxic T cell function independent of effector differentiation. Immunity 25, 129–141 (2006)

    CAS  Article  Google Scholar 

  22. 22

    Whelan, S. P., Ball, L. A., Barr, J. N. & Wertz, G. T. Efficient recovery of infectious vesicular stomatitis virus entirely from cDNA clones. Proc. Natl Acad. Sci. USA 92, 8388–8392 (1995)

    ADS  CAS  Article  Google Scholar 

  23. 23

    Van Rooijen, N. & Sanders, A. Liposome mediated depletion of macrophages: mechanism of action, preparation of liposomes and applications. J. Immunol. Methods 174, 83–93 (1994)

    CAS  Article  Google Scholar 

  24. 24

    Iannacone, M. et al. Platelets mediate cytotoxic T lymphocyte-induced liver damage. Nature Med. 11, 1167–1169 (2005)

    CAS  Article  Google Scholar 

  25. 25

    Shao, C., Liu, M., Wu, X. & Ding, F. Time-dependent expression of myostatin RNA transcript and protein in gastrocnemius muscle of mice after sciatic nerve resection. Microsurgery 27, 487–493 (2007)

    Article  Google Scholar 

  26. 26

    Iannacone, M. et al. Platelets prevent IFN-α/β-induced lethal hemorrhage promoting CTL-dependent clearance of lymphocytic choriomeningitis virus. Proc. Natl Acad. Sci. USA 105, 629–634 (2008)

    ADS  CAS  Article  Google Scholar 

Download references


We thank G. Cheng and M. Flynn for technical support; J. Alton for secretarial assistance; D. Cureton for help and advice with VSV preparations; H. Leung for help with image quantification; R. M. Zinkernagel and H. Hengartner for providing tg7 mice; R. Bronson for help with reading neuropathology; S. Cohen for advice on nerve staining; N. van Rooijen for clodronate liposomes; and the members of the von Andrian laboratory for discussion. This work was supported by National Institutes of Health (NIH) grants AI069259, AI072252, AI078897 and AR42689 (to U.H.v.A.), the Giovanni Armenise-Harvard Foundation (to M.I.) and a NIH T32 Training Grant in Hematology (to E.A.M.).

Author information




M.I., E.A.M. and U.H.v.A. designed the study. M.I., E.A.M., E.T., L.B. and T.J. performed experiments. M.I., E.A.M., E.T. and L.B. collected and analysed data. S.P.W. provided reagents and performed the RT–PCR experiment. S.E.H. contributed to the nerve imaging. L.G.G. provided mice and gave conceptual advice. M.I., E.A.M. and U.H.v.A. wrote the manuscript. M.I. and E.A.M contributed equally to this work.

Corresponding authors

Correspondence to Matteo Iannacone or Ulrich H. von Andrian.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-13 with legends and legends for Supplementary Movies 1-2. (PDF 1161 kb)

Supplementary Movie 1

This movie shows a three-dimensional rotation view followed by Z-stack projection of the MP-IVM stack used to generate Fig. 2e (see Supplementary Information file for full legend). (MOV 12971 kb)

Supplementary Movie 2

This movie shows a three-dimensional rotation view followed by Z-stack projection of the MP-IVM stack used to generate Fig. 2f (see Supplementary Information file for full legend). (MOV 8989 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Iannacone, M., Moseman, E., Tonti, E. et al. Subcapsular sinus macrophages prevent CNS invasion on peripheral infection with a neurotropic virus. Nature 465, 1079–1083 (2010).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing