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

Abstract

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.

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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.

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Acknowledgements

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.

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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)

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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). https://doi.org/10.1038/nature07591

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