A Protective Role for the Lectin CD169/Siglec-1 against a Pathogenic Murine Retrovirus
Abstract
Lymph- and blood-borne retroviruses exploit CD169/Siglec-1-mediated capture by subcapsular sinus and marginal zone metallophilic macrophages for trans-infection of permissive lymphocytes. However, the impact of CD169-mediated virus capture on retrovirus dissemination and pathogenesis in vivo is unknown. In a murine model of the splenomegaly-inducing retrovirus Friend virus complex (FVC) infection, we find that while CD169 promoted draining lymph node infection, it limited systemic spread to the spleen. At the spleen, CD169-expressing macrophages captured incoming blood-borne retroviruses and limited their spread to the erythroblasts in the red pulp where FVC manifests its pathogenesis. CD169-mediated retroviral capture activated conventional dendritic cells 1 (cDC1s) and promoted cytotoxic CD8+ T cell responses, resulting in efficient clearing of FVC-infected cells. Accordingly, CD169 blockade led to higher viral loads and accelerated death in susceptible mouse strains. Thus, CD169 plays a protective role during FVC pathogenesis by reducing viral dissemination to erythroblasts and eliciting an effective cytotoxic T lymphocyte response via cDC1s.
Additional Information
© 2018 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Received 10 June 2018, Revised 8 October 2018, Accepted 5 November 2018, Available online 27 December 2018. This work was supported by NIH grants R01 CA098727 to W.M. and P50GM082545 to W.M. and P.B.J.; the Flow Cytometry Shared Resource of the Yale Cancer CenterP30 CA016359, Yale Center for Cellular and Molecular ImagingS10 OD020142, R21 AI112418 to M.L.S.; funding from the Francis Crick Institute (FC001099) to G.K.; and a fellowship from the China Scholarship Council – Yale World Scholars to R.P. We thank Stephanie Eisenbarth for providing Batf3^(−/−) mice, and Frank Malik, Leonard Evans, and Kim Hasenkrug for suggestions and providing reagents. Author Contributions: P.D.U. and R.P. contributed equally to executing experiments, data analysis, and figure generation. P.D.U., R.P., and W.M. shared the conceptualization, experimental design, interpretation, and manuscript preparation. K.A.H. generated constructs and mouse strains. M.S.L. carried out electron tomography. J.D.V. helped with cryo-sectioning of tissues. B.S.B., M.L.S., and G.K. provided all the reagents, protocols, and EF4.1 mouse strains for carrying out FVC work. M.L.S., X.S., P.J.B., and G.K. contributed to interpretation and discussion of the work. The authors declare no competing interests.Attached Files
Published - 1-s2.0-S1931312818305936-main.pdf
Supplemental Material - 1-s2.0-S1931312818305936-mmc1.pdf
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Additional details
- PMCID
- PMC6331384
- Eprint ID
- 91977
- Resolver ID
- CaltechAUTHORS:20190102-092233964
- NIH
- R01 CA098727
- NIH
- P50 GM082545
- NIH
- P30 CA016359
- NIH
- S10 OD020142
- NIH
- R21 AI112418
- Francis Crick Institute
- FC001099
- China Scholarship Council
- Created
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2019-01-02Created from EPrint's datestamp field
- Updated
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2022-02-24Created from EPrint's last_modified field