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.

Myelomonocytic cell recruitment causes fatal CNS vascular injury during acute viral meningitis


Lymphocytic choriomeningitis virus1 infection of the mouse central nervous system (CNS) elicits fatal immunopathology through blood–brain barrier breakdown2 and convulsive seizures3. Although lymphocytic-choriomeningitis-virus-specific cytotoxic T lymphocytes (CTLs) are essential for disease4, their mechanism of action is not known. To gain insights into disease pathogenesis, we observed the dynamics of immune cells in the meninges by two-photon microscopy. Here we report visualization of motile CTLs and massive secondary recruitment of pathogenic monocytes and neutrophils that were required for vascular leakage and acute lethality. CTLs expressed multiple chemoattractants capable of recruiting myelomonocytic cells. We conclude that a CD8+ T-cell-dependent disorder can proceed in the absence of direct T-cell effector mechanisms and rely instead on CTL-recruited myelomonocytic cells.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: CTL localization and dynamics in the meninges of LCMV-infected mice.
Figure 2: LCMV infection of ER-TR7 + stromal cells in the meninges.
Figure 3: Analysis of mononuclear cell infiltrate and effector mechanisms during LCMV-induced meningitis.
Figure 4: Recruitment of myelomonocytic cells into CNS and the relationship to meningeal vascular injury.


  1. Kang, S. S. & McGavern, D. B. Lymphocytic choriomeningitis infection of the central nervous system. Front. Biosci. 13, 4529–4543 (2008)

    CAS  Article  Google Scholar 

  2. Marker, O., Nielsen, M. H. & Diemer, N. H. The permeability of the blood–brain barrier in mice suffering from fatal lymphocytic choriomeningitis virus infection. Acta Neuropathol. 63, 229–239 (1984)

    CAS  Article  Google Scholar 

  3. Camenga, D. L., Walker, D. H. & Murphy, F. A. Anticonvulsant prolongation of survival in adult murine lymphocytic choriomeningitis. I. Drug treatment and virologic studies. J. Neuropathol. Exp. Neurol. 36, 9–20 (1977)

    CAS  Article  Google Scholar 

  4. Fung-Leung, W. P., Kundig, T. M., Zinkernagel, R. M. & Mak, T. W. Immune response against lymphocytic choriomeningitis virus infection in mice without CD8 expression. J. Exp. Med. 174, 1425–1429 (1991)

    CAS  Article  Google Scholar 

  5. Bajenoff, M. et al. Stromal cell networks regulate lymphocyte entry, migration, and territoriality in lymph nodes. Immunity 25, 989–1001 (2006)

    CAS  Article  Google Scholar 

  6. Bromley, S. K., Peterson, D. A., Gunn, M. D. & Dustin, M. L. Cutting edge: hierarchy of chemokine receptor and TCR signals regulating T cell migration and proliferation. J. Immunol. 165, 15–19 (2000)

    CAS  Article  Google Scholar 

  7. Storm, P., Bartholdy, C., Sorensen, M. R., Christensen, J. P. & Thomsen, A. R. Perforin-deficient CD8+ T cells mediate fatal lymphocytic choriomeningitis despite impaired cytokine production. J. Virol. 80, 1222–1230 (2006)

    CAS  Article  Google Scholar 

  8. Johnson, E. D., Monjan, A. A. & Morse, H. C. Lack of B-cell participation in acute lymphocyte choriomeningitis disease of the central nervous system. Cell. Immunol. 36, 143–150 (1978)

    CAS  Article  Google Scholar 

  9. Leist, T. P., Cobbold, S. P., Waldmann, H., Aguet, M. & Zinkernagel, R. M. Functional analysis of T lymphocyte subsets in antiviral host defense. J. Immunol. 138, 2278–2281 (1987)

    CAS  PubMed  Google Scholar 

  10. Tepper, R. I., Coffman, R. L. & Leder, P. An eosinophil-dependent mechanism for the antitumor effect of interleukin-4. Science 257, 548–551 (1992)

    ADS  CAS  Article  Google Scholar 

  11. Kurihara, T., Warr, G., Loy, J. & Bravo, R. Defects in macrophage recruitment and host defense in mice lacking the CCR2 chemokine receptor. J. Exp. Med. 186, 1757–1762 (1997)

    CAS  Article  Google Scholar 

  12. Marchi, N. et al. Seizure-promoting effect of blood–brain barrier disruption. Epilepsia 48, 732–742 (2007)

    CAS  Article  Google Scholar 

  13. Asensio, V. C. & Campbell, I. L. Chemokine gene expression in the brains of mice with lymphocytic choriomeningitis. J. Virol. 71, 7832–7840 (1997)

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Kaech, S. M., Hemby, S., Kersh, E. & Ahmed, R. Molecular and functional profiling of memory CD8 T cell differentiation. Cell 111, 837–851 (2002)

    CAS  Article  Google Scholar 

  15. Wherry, E. J. et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27, 670–684 (2007)

    CAS  Article  Google Scholar 

  16. Andersen, I. H., Marker, O. & Thomsen, A. R. Breakdown of blood–brain barrier function in the murine lymphocytic choriomeningitis virus infection mediated by virus-specific CD8+ T cells. J. Neuroimmunol. 31, 155–163 (1991)

    CAS  Article  Google Scholar 

  17. Doherty, P. C., Allan, J. E., Lynch, F. & Ceredig, R. Dissection of an inflammatory process induced by CD8+ T cells. Immunol. Today 11, 55–59 (1990)

    CAS  Article  Google Scholar 

  18. Walker, D. H., Camenga, D. L., Whitfield, S. & Murphy, F. A. Anticonvulsant prolongation of survival in adult murine lymphocytic choriomeningitis. II. Ultrastructural observations of pathogenetic events. J. Neuropathol. Exp. Neurol. 36, 21–40 (1977)

    CAS  Article  Google Scholar 

  19. Wedmore, C. V. & Williams, T. J. Control of vascular permeability by polymorphonuclear leukocytes in inflammation. Nature 289, 646–650 (1981)

    ADS  CAS  Article  Google Scholar 

  20. Bjork, J. & Arfors, K. E. Oxygen free radicals and leukotriene B4 induced increase in vascular leakage is mediated by polymorphonuclear leukocytes. Agents Actions Suppl. 1163–72 (1982)

  21. Rosengren, S., Ley, K. & Arfors, K. E. Dextran sulfate prevents LTB4-induced permeability increase, but not neutrophil emigration, in the hamster cheek pouch. Microvasc. Res. 38, 243–254 (1989)

    CAS  Article  Google Scholar 

  22. Hixenbaugh, E. A. et al. Stimulated neutrophils induce myosin light chain phosphorylation and isometric tension in endothelial cells. Am. J. Physiol. 273, H981–H988 (1997)

    CAS  PubMed  Google Scholar 

  23. Sekido, N. et al. Prevention of lung reperfusion injury in rabbits by a monoclonal antibody against interleukin-8. Nature 365, 654–657 (1993)

    ADS  CAS  Article  Google Scholar 

  24. Herwald, H. et al. M protein, a classical bacterial virulence determinant, forms complexes with fibrinogen that induce vascular leakage. Cell 116, 367–379 (2004)

    CAS  Article  Google Scholar 

  25. Tacke, F. et al. Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J. Clin. Invest. 117, 185–194 (2007)

    CAS  Article  Google Scholar 

  26. Maus, U. et al. The role of CC chemokine receptor 2 in alveolar monocyte and neutrophil immigration in intact mice. Am. J. Respir. Crit. Care Med. 166, 268–273 (2002)

    Article  Google Scholar 

  27. Ancuta, P., Moses, A. & Gabuzda, D. Transendothelial migration of CD16+monocytes in response to fractalkine under constitutive and inflammatory conditions. Immunobiology 209, 11–20 (2004)

    CAS  Article  Google Scholar 

  28. Stamatovic, S. M. et al. Monocyte chemoattractant protein-1 regulation of blood–brain barrier permeability. J. Cereb. Blood Flow Metab. 25, 593–606 (2005)

    CAS  Article  Google Scholar 

  29. Intlekofer, A. M. et al. Anomalous type 17 response to viral infection by CD8+ T cells lacking T-bet and eomesodermin. Science 321, 408–411 (2008)

    ADS  CAS  Article  Google Scholar 

  30. Beal, A. M. et al. Protein kinase Ctheta regulates stability of the peripheral adhesion ring junction and contributes to the sensitivity of target cell lysis by CTL. J. Immunol. 181, 4815–4824 (2008)

    CAS  Article  Google Scholar 

  31. McGavern, D. B., Christen, U. & Oldstone, M. B. Molecular anatomy of antigen-specific CD8+ T cell engagement and synapse formation in vivo. Nature Immunol. 3, 918–925 (2002)

    CAS  Article  Google Scholar 

  32. Faust, N., Varas, F., Kelly, L. M., Heck, S. & Graf, T. Insertion of enhanced green fluorescent protein into the lysozyme gene creates mice with green fluorescent granulocytes and macrophages. Blood 96, 719–726 (2000)

    CAS  PubMed  Google Scholar 

  33. Crozat, K. et al. Jinx, an MCMV susceptibility phenotype caused by disruption of Unc13d: a mouse model of type 3 familial hemophagocytic lymphohistiocytosis. J. Exp. Med. 204, 853–863 (2007)

    CAS  Article  Google Scholar 

  34. Revell, P. A. et al. Granzyme B and the downstream granzymes C and/or F are important for cytotoxic lymphocyte functions. J. Immunol. 174, 2124–2131 (2005)

    CAS  Article  Google Scholar 

  35. Lauterbach, H., Zuniga, E. I., Truong, P., Oldstone, M. B. A. & McGavern, D. B. Adoptive immunotherapy induces CNS dendritic cell recruitment and antigen presentation during clearance of a persistent viral infection. J. Exp. Med. 203, 1963–1975 (2006)

    CAS  Article  Google Scholar 

  36. Kim, J. V. & Dustin, M. L. Innate response to focal necrotic injury inside the blood–brain barrier. J. Immunol. 177, 5269–5277 (2006)

    CAS  Article  Google Scholar 

Download references


This work was supported by National Institutes of Health grants AI070967-01 (D.B.M.), AI055037 (M.L.D.), a grant from The Burroughs Wellcome Fund (D.B.M.) and the Dana Foundation (M.L.D.). S.S.K. was supported by a National Institutes of Health training grant NS041219-06 and is presently supported by a National Research Service Award (NS061447-01), and J.V.K. is supported by a Multiple Sclerosis Society Center Grant. We thank C. Yau for technical support and the Scripps DNA Array core for their assistance with the gene array experiment.

Author information

Authors and Affiliations


Corresponding authors

Correspondence to Michael L. Dustin or Dorian B. McGavern.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-10 with Legends and Supplementary Movie Legends 1-5. (PDF 3015 kb)

Supplementary Movie 1

Supplementary Movie 1 shows CTL localization and dynamics in the meninges. (MOV 9875 kb)

Supplementary Movie 2

Supplementary Movie 2 shows LCMV infection of fibroblast-like cells around meningeal blood vessels. (MOV 6691 kb)

Supplementary Movie 3

Supplementary Movie 3 shows loss of vascular integrity during meningitis is not associated with CTL activities (MOV 8102 kb)

Supplementary Movie 4

Supplementary Movie 4 shows that Myelomonocytic extravasation accompanies a sustained loss in vascular integrity. (MOV 9000 kb)

Supplementary Movie 5

Supplementary Movie 5 shows that Perivascular myelomonocytic cell aggregation accompanies transient vascular leakage. (MOV 8511 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kim, J., Kang, S., Dustin, M. et al. Myelomonocytic cell recruitment causes fatal CNS vascular injury during acute viral meningitis. Nature 457, 191–195 (2009).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


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