Central nervous system stromal cells control local CD8 + T cell responses during virus-induced neuroinflammation.
Open accessAbstract
Stromal cells generate a complex cellular scaffold that provides specialized microenvironments for lymphocyte activation in secondary lymphoid organs. Here, we assessed whether local activation of stromal cells in the central nervous system (CNS) is mandatory to transfer immune recognition from secondary lymphoid organs into the infected tissue. We report that neurotropic virus infection in mice triggered the establishment of such stromal cell niches in the CNS. CNS stromal cell activation was dominated by a rapid and vigorous production of CC-motif chemokine receptor (CCR) 7 ligands CCL19 and CCL21 by vascular endothelial cells and adjacent fibroblastic reticular cell (FRC)-like cells in the perivascular space. Moreover, CCR7 ligands produced by CNS stromal cells were crucial to support recruitment and local re-activation of antiviral CD8(+) T cells and to protect the host from lethal neuroinflammatory disease, indicating that CNS stromal cells generate confined microenvironments that control protective T cell immunity.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
During murine CNS infections, including mouse hepatitis virus and LCMV Armstrong, there is an influx into the brain and subarachnoid space of CD8+ T cells, monocytes and neutrophils into the meninges quickly after infection.
“during murine CNS infections, including mouse hepatitis virus, a murine coronavirus (strains Srr7, cl-2, and A59), the Armstrong strain of lymphocytic choriomeningitis virus (LCMV), all show there is an influx into the brain and subarachnoid space of CD8+ T cells, monocytes and neutrophils into the meninges quickly after infection”
From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Cupovic et al., 2016
In the mouse model of corona virus MHV A59 infection, production of cytokines CCL19 and CCL21 by a meningeal fibroblasts subpopulation, marked by ER-TR7 antigen, and podoplanin, work to recruit anti-viral CD8+ T cells.
“in the mouse model of corona virus MHV A59 infection, production of cytokines CCL19 and CCL21 by a meningeal fibroblasts subpopulation, marked by ER-TR7 antigen, and podoplanin, work to recruit anti-viral CD8+ T cells”
From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Cupovic et al., 2016
Timely recruitment of these T cells is required to prevent fatal CNS disease after infection with this virus.
“Timely recruitment of these T cells is required to prevent fatal CNS disease after infection with this virus.”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [153]
After coronavirus infection, endothelial and fibroblastic reticular cells in the meninges release CCL19 and CCL21 to recruit and reactivate antiviral CCR7+ CD8+ T cells.
“After coronavirus infection, endothelial and fibroblastic reticular cells in the meninges release CCL19 and CCL21 to recruit and reactivate antiviral CCR7+ CD8+ T cells (153).”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [153]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Structural and functional features of central nervous system lymphatic vessels
Louveau, A., Smirnov, I., Keyes, T. J., Eccles, J. D., Rouhani, S. J., Peske, J. D., Derecki, N. C., Castle, D., Mandell, J. W., Lee, K. S., et al. (2015) · Nature · doi:10.1038/nature14432 · Cited by 4,413 · see citing works
Förster, R., Schubel, A., Breitfeld, D., Kremmer, E., Renner‐Müller, I., Wolf, E., & Lipp, M. (1999) · Cell · doi:10.1016/s0092-8674(00)80059-8 · Cited by 2,348 · see citing works
A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules
Aspelund, A., Antila, S., Proulx, S. T., Karlsen, T. V., Karaman, S., Detmar, M., Wiig, H., & Alitalo, K. (2015) · Journal of Experimental Medicine · doi:10.1084/jem.20142290 · Cited by 2,198 · see citing works
CCR7 and its ligands: balancing immunity and tolerance
Förster, R., Davalos-Misslitz, A. C., & Rot, A. (2008) · Nature Reviews Immunology · doi:10.1038/nri2297 · Cited by 1,410 · see citing works
Stromal cell networks regulate lymphocyte entry, migration, and territoriality in lymph nodes.
Bajénoff, M., Egen, J., Koo, L. Y., Laugier, J., Brau, F., Glaichenhaus, N., & Germain, R. N. (2006) · Immunity · doi:10.1016/j.immuni.2006.10.011 · Cited by 1,022 · see citing works
Gunn, M. D., Kyuwa, S., Tam‐Amersdorfer, C., Kakiuchi, T., Matsuzawa, A., Williams, L. T., & Nakano, H. (1999) · The Journal of Experimental Medicine · doi:10.1084/jem.189.3.451 · Cited by 1,019 · see citing works
Gunn, M. D., Tangemann, K., Tam‐Amersdorfer, C., Cyster, J. G., Rosen, S. D., & Williams, L. T. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.1.258 · Cited by 1,001 · see citing works
The anatomical and cellular basis of immune surveillance in the central nervous system
Ransohoff, R. M., & Engelhardt, B. (2012) · Nature reviews. Immunology · doi:10.1038/nri3265 · Cited by 975 · see citing works
Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells
Link, A., Vogt, T. K., Favre, S., Britschgi, M. R., Acha‐Orbea, H., Hinz, B., Cyster, J. G., & Luther, S. A. (2007) · Nature Immunology · doi:10.1038/ni1513 · Cited by 934 · see citing works
A Cre-inducible diphtheria toxin receptor mediates cell lineage ablation after toxin administration
Buch, T., Heppner, F. L., Tertilt, C., Heinen, T. J. A. J., Kremer, M., Wunderlich, F. T., Jung, S., & Waisman, A. (2005) · Nature Methods · doi:10.1038/nmeth762 · Cited by 922 · see citing works
Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis
Greter, M., Heppner, F. L., Lemos, M. P., Odermatt, B. M., Goebels, N., Laufer, T., Noelle, R. J., & Becher, B. (2005) · Nature Medicine · doi:10.1038/nm1197 · Cited by 862 · see citing works
What is immune privilege (not)?
Galea, I., Bechmann, I., & Perry, V. H. (2007) · Trends in Immunology · doi:10.1016/j.it.2006.11.004 · Cited by 768 · see citing works
Self-citationEctopic lymphoid-like structures in infection, cancer and autoimmunity
Pitzalis, C., Jones, G. W., Bombardieri, M., & Jones, S. A. (2014) · Nature reviews. Immunology · doi:10.1038/nri3700 · Cited by 700 · see citing works
Coronavirus Spike Proteins in Viral Entry and Pathogenesis
Gallagher, T. M., & Buchmeier, M. J. (2001) · Virology · doi:10.1006/viro.2000.0757 · Cited by 658 · see citing works
Malhotra, D., Fletcher, A. L., Astarita, J. L., Lukacs‐Kornek, V., Tayalia, P., González, S., Elpek, K. G., Chang, S. K., Knoblich, K., Hemler, M. E., et al. (2012) · Nature Immunology · doi:10.1038/ni.2262 · Cited by 454 · see citing works
Coronavirus infection of the central nervous system: host–virus stand-off
Bergmann, C. C., Lane, T. E., & Stohlman, S. A. (2006) · Nature Reviews Microbiology · doi:10.1038/nrmicro1343 · Cited by 398 · see citing works
Ghoshal, A., Das, S., Ghosh, S. K., Mishra, M. K., Sharma, V., Koli, P., Sen, E., & Basu, A. (2007) · Glia · doi:10.1002/glia.20474 · Cited by 387 · see citing works
Molecular mechanisms involved in T cell migration across the blood–brain barrier
Engelhardt, B. (2006) · Journal of Neural Transmission · doi:10.1007/s00702-005-0409-y · Cited by 344 · see citing works
Scandella, E., Bolinger, B., Lattmann, E., et al. (2008) · Nature Immunology · doi:10.1038/ni.1605 · Cited by 342 · see citing works
Development of Secondary Lymphoid Organs
Randall, T. D., Carragher, D. M., & Rangel‐Moreno, J. (2008) · Annual Review of Immunology · doi:10.1146/annurev.immunol.26.021607.090257 · Cited by 339 · see citing works
Myelomonocytic cell recruitment causes fatal CNS vascular injury during acute viral meningitis
Kim, J. V., Kang, S. S., Dustin, M. L., & McGavern, D. B. (2009) · Nature · doi:10.1038/nature07591 · Cited by 326 · see citing works
Comerford, I., Harata‐Lee, Y., Bunting, M. D., Whyte, C. E., Kara, E. E., & McColl, S. R. (2013) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2013.03.001 · Cited by 289 · see citing works
B cell homeostasis and follicle confines are governed by fibroblastic reticular cells
Cremasco, V., Woodruff, M. C., Onder, L., Cupovic, J., Nieves-Bonilla, J. M., Schildberg, F. A., Chang, J. E., Cremasco, F., Harvey, C. J., Wucherpfennig, K. W., et al. (2014) · Nature Immunology · doi:10.1038/ni.2965 · Cited by 278 · see citing works
Self-citationExpression of CCR7 in multiple sclerosis: implications for CNS immunity
Kivisäkk, P., Mahad, D. J., Callahan, M. K., Sikora, K., Trebst, C., Tucky, B., Wujek, J., Ravid, R., Staugaitis, S. M., Lassmann, H., et al. (2004) · Annals of Neurology · doi:10.1002/ana.20049 · Cited by 267 · see citing works
Browning, J. L., Allaire, N., Ngam-ek, A., Notidis, E., Hunt, J., Perrin, S., & Fava, R. A. (2005) · Immunity · doi:10.1016/j.immuni.2005.10.002 · Cited by 265 · see citing works
Form follows function: lymphoid tissue microarchitecture in antimicrobial immune defence
Junt, T., Scandella, E., & Ludewig, B. (2008) · Nature reviews. Immunology · doi:10.1038/nri2414 · Cited by 264 · see citing works
Self-citationChai, Q., Onder, L., Scandella, E., Gil‐Cruz, C., Perez‐Shibayama, C., Cupovic, J., Danuser, R., Sparwasser, T. D., Luther, S. A., Thiel, V., et al. (2013) · Immunity · doi:10.1016/j.immuni.2013.03.012 · Cited by 250 · see citing works
Self-citationNakano, H., & Gunn, M. D. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.166.1.361 · Cited by 212 · see citing works
Rangel‐Moreno, J., Moyron‐Quiroz, J., Hartson, L., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0700591104 · Cited by 186 · see citing works
Onder, L., Danuser, R., Scandella, E., et al. (2013) · The Journal of Experimental Medicine · doi:10.1084/jem.20121462 · Cited by 169 · see citing works
Self-citationWilson, E. H., Harris, T. H., Mrass, P., John, B., Wojno, E. D. T., Wu, G. F., Pepper, M., Wherry, E. J., Dzierzinski, F., Roos, D. S., et al. (2009) · Immunity · doi:10.1016/j.immuni.2008.12.013 · Cited by 167 · see citing works
Cabezas, S. C., Serafini, B., & Aloisi, F. (2003) · Brain Pathology · doi:10.1111/j.1750-3639.2003.tb00005.x · Cited by 153 · see citing works
Nindl, V., Maier, R., Ratering, D., de Giuli, R., Züst, R., Thiel, V., Scandella, E., Padova, F. D., Köpf, M., Rudin, M., et al. (2012) · European Journal of Immunology · doi:10.1002/eji.201142209 · Cited by 140 · see citing works
Self-citationKrumbholz, M., Theil, D. J., Steinmeyer, F., Cepok, S., Hemmer, B., Hofbauer, M., Farina, C., Derfuss, T. J., Junker, A., Arzberger, T., et al. (2007) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2007.07.024 · Cited by 136 · see citing works
Effect of olfactory bulb ablation on spread of a neurotropic coronavirus into the mouse brain.
Perlman, S. M., Evans, G., & Afifi, A. K. (1990) · The Journal of Experimental Medicine · doi:10.1084/jem.172.4.1127 · Cited by 129 · see citing works
The Role of Chemokines during Viral Infection of the CNS
Hosking, M., & Lane, T. E. (2010) · PLoS Pathogens · doi:10.1371/journal.ppat.1000937 · Cited by 106 · see citing works
Lo, J. C., Chin, R., Lee, Y., Kang, H.-S., Wang, Y., Weinstock, J. V., Banks, T. A., Ware, C. F., Franzoso, G., & Fu, Y. (2003) · Journal of Clinical Investigation · doi:10.1172/jci19188 · Cited by 106 · see citing works
Mionnet, C., Sanos, S. L., Mondor, I., et al. (2011) · Blood · doi:10.1182/blood-2011-07-367409 · Cited by 91 · see citing works
Impact of CCR7 on Priming and Distribution of Antiviral Effector and Memory CTL
Junt, T., Scandella, E., Förster, R., Krebs, P., Krautwald, S., Lipp, M., Hengartner, H., & Ludewig, B. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.173.11.6684 · Cited by 84 · see citing works
Self-citationPashenkov, M. V., Söderström, M. B., & Link, H. (2003) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(02)00441-1 · Cited by 83 · see citing works
Endothelial induction of the T-cell chemokine CCL21 in T-cell autoimmune diseases
Christopherson, K. W., Hood, A. F., Travers, J. B., Ramsey, H. E., & Hromas, R. (2003) · Blood · doi:10.1182/blood-2002-05-1586 · Cited by 64 · see citing works
Antiviral Immune Responses in the Absence of Organized Lymphoid T Cell Zones in plt/plt Mice
Junt, T., Nakano, H., Dumrese, T., et al. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.168.12.6032 · Cited by 63 · see citing works
Bosè, F., Petti, L., Diani, M., Moscheni, C., Molteni, S., Altomare, A., Rossi, R. L., Talarico, D., Fontana, R., Russo, V. E. A., et al. (2013) · American Journal Of Pathology · doi:10.1016/j.ajpath.2013.04.021 · Cited by 59 · see citing works
Bagai, R. K., Valujskikh, A., Canaday, D., Bailey, E., Lalli, P., Harding, C., & Heeger, P. (2005) · Journal of Immunology · doi:10.4049/jimmunol.174.12.7711 · Cited by 59 · see citing works
CCR7-Dependent Immunity during Acute Toxoplasma gondii Infection
Noor, S., Habashy, A., Nance, J. P., Clark, R. T., Nemati, K., Carson, M. J., & Wilson, E. H. (2010) · Infection and Immunity · doi:10.1128/iai.01314-09 · Cited by 56 · see citing works
Burke, M. L., McManus, D. P., Ramm, G. A., Duke, M., Li, Y. S., Jones, M. K., & Gobert, G. N. (2010) · PLoS neglected tropical diseases · doi:10.1371/journal.pntd.0000686 · Cited by 52 · see citing works
The great balancing act: regulation and fate of antiviral T‐cell interactions
Moseman, E. A., & McGavern, D. B. (2013) · Immunological Reviews · doi:10.1111/imr.12093 · Cited by 27 · see citing works
T helper cell- and CD40-dependent germline IgM prevents chronic virus-induced demyelinating disease
Gil‐Cruz, C., Perez‐Shibayama, C., Firner, S., Waisman, A., Bechmann, I., Thiel, V., Cervantes‐Barragán, L., & Ludewig, B. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1115154109 · Cited by 26 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
- Alt C. Laschinger M. Engelhardt B. Functional expression of the lymphoid chemokines CCL19 (ELC) and CCL 21 (SLC) at the blood-brain barrier suggests their involvement in G-protein-dependent lymphocyte recruitment into the central nervous system during experimental autoimmune encephalomyelitis Eur. J. Immunol. 32 2002 2133 2144 12209625
Cited by
Sorted by citations
The anatomy and immunology of vasculature in the central nervous system
Mastorakos, P., & McGavern, D. (2019) · Science Immunology · doi:10.1126/sciimmunol.aav0492 · Cited by 333 · see citing works
Two distinct immunopathological profiles in autopsy lungs of COVID-19
Nienhold, R., Ciani, Y., Koelzer, V. H., Tzankov, A., Haslbauer, J. D., Menter, T., Schwab, N., Henkel, M., Frank, A., Zsikla, V., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-18854-2 · Cited by 246 · see citing works
Molecular characterization of perivascular drainage pathways in the murine brain
Hannocks, M.-J., Pizzo, M. E., Huppert, J., Deshpande, T., Abbott, N. J., Thorne, R. G., & Sorokin, L. (2018) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x17749689 · Cited by 201 · see citing works
A Binary Cre Transgenic Approach Dissects Microglia and CNS Border-Associated Macrophages
Kim, J.-S., Kolesnikov, M., Peled-Hajaj, S., Scheyltjens, I., Xia, Y., Trzebanski, S., Haimon, Z., Shemer, A., Lubart, A., Van Hove, H., et al. (2021) · Immunity · doi:10.1016/j.immuni.2020.11.007 · Cited by 176 · see citing works
Neuroinflammation During RNA Viral Infections
Klein, R. S., Garber, C., Funk, K. E., Salimi, H., Soung, A., Kanmogne, M., Manivasagam, S., Agner, S., & Cain, M. (2019) · Annual Review of Immunology · doi:10.1146/annurev-immunol-042718-041417 · Cited by 160 · see citing works
Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease
Derk, J., Jones, H. E., Como, C., Pawlikowski, B., & Siegenthaler, J. A. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.703944 · Cited by 120 · see citing works
“…strain of lymphocytic choriomeningitis virus (LCMV), all show there is an influx into the brain and subarachnoid space of CD8+ T cells, monocytes and neutrophils into the meninges quickly after infection (Kim et al., 2009; Takatsuki et al., 2009; Cupovic et al., 2016; Watanabe et al., 2016).”
BackgroundImmunological defense of CNS barriers against infections
Ampie, L., & McGavern, D. B. (2022) · Immunity · doi:10.1016/j.immuni.2022.04.012 · Cited by 63 · see citing works
Stromal cell niches in the inflamed central nervous system.
Pikor, N. B., Cupovic, J., Onder, L., Gommerman, J. L., & Ludewig, B. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1601566 · Cited by 33 · see citing works
Self-citationShaping of Peripheral T Cell Responses by Lymphatic Endothelial Cells
Humbert, M., Hugues, S., & Dubrot, J. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00684 · Cited by 32 · see citing works
- Authors
- Cupovic, J., Onder, L., Gil-Cruz, C., Weiler, E., Caviezel-Firner, S., Perez-Shibayama, C., Rülicke, T., Bechmann, I., & Ludewig, B.
- Affiliations
- Kantonsspital St. Gallen (CH)
- Universität Ulm (DE)
- University of Veterinary Medicine Vienna (AT)
- Leipzig University (DE)
- Corresponding author
- Ludewig, Burkhard
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2016-03
- Volume
- 44
- Issue
- 3
- Pages
- 622-633
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC7111064
- OpenAlex
- W2273608634
- Cited by
- 98
- References
- 49
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 10 · 2023: 11 · 2022: 5 · 2021: 17 · 2020: 10 · 2019: 8 · 2018: 8 · 2017: 15 · 2016: 3
- FWCI
- 6.21
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Digital Library (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (146133)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Keywords
- CD8+ T cells, neuroinflammation, neurotropic viruses, CCL19, CCL21, fibroblastic reticular cells, vascular endothelial cells, T cell reactivation, T cell recruitment, perivascular niche, antiviral immunity, secondary lymphoid organs
- MeSH terms
- Animals, Cell Movement, Central Nervous System, Endothelium, Vascular, Hepatitis A, Immunity, Cellular, Mice, Inbred C57BL, Mice, Transgenic, Stromal Cells, Mice, Knockout, CD8-Positive T-Lymphocytes, Neurogenic Inflammation, Hepatitis A virus, Mice, Receptors, CCR7, Chemokine CCL19, Chemokine CCL21, Viral Tropism, Immunomodulation, Cellular Microenvironment
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
