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.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
von Andrian, U. H. & Mempel, T. R. Homing and cellular traffic in lymph nodes. Nature Rev. Immunol. 3, 867–878 (2003)
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)
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)
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)
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)
Hangartner, L., Zinkernagel, R. M. & Hengartner, H. Antiviral antibody responses: the two extremes of a wide spectrum. Nature Rev. Immunol. 6, 231–243 (2006)
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)
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)
Muller, U. et al. Functional role of type I and type II interferons in antiviral defense. Science 264, 1918–1921 (1994)
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)
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)
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)
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)
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)
Asselin-Paturel, C. et al. Mouse type I IFN-producing cells are immature APCs with plasmacytoid morphology. Nature Immunol. 2, 1144–1150 (2001)
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)
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)
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)
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)
Maloy, K. J. et al. Qualitative and quantitative requirements for CD4+ T cell-mediated antiviral protection. J. Immunol. 162, 2867–2874 (1999)
Mempel, T. R. et al. Regulatory T cells reversibly suppress cytotoxic T cell function independent of effector differentiation. Immunity 25, 129–141 (2006)
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)
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)
Iannacone, M. et al. Platelets mediate cytotoxic T lymphocyte-induced liver damage. Nature Med. 11, 1167–1169 (2005)
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)
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)
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.).
The authors declare no competing financial interests.
This file contains Supplementary Figures 1-13 with legends and legends for Supplementary Movies 1-2. (PDF 1161 kb)
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)
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)
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). https://doi.org/10.1038/nature09118
Nature Communications (2020)
Nature Communications (2020)
Spatiotemporal regulation of type I interferon expression determines the antiviral polarization of CD4+ T cells
Nature Immunology (2020)
Nature Immunology (2019)
Nature Reviews Immunology (2018)