Impact of macrophage and dendritic cell subset elimination on antiviral immunity, viral clearance and production of type 1 interferon

Richard P. Ciavarra, Lisa Taylor, Amy R. Greene, Nazita Yousefieh, Dale Horeth, Nico Van Rooijen, Christina Steel, Betsy Gregory, Mark Birkenbach, Margaret Sekellick

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

We report herein that vesicular stomatitis virus (VSV) induced a concurrent primary Th1 (T helper 1) and Th2 cytokine response detectable ex vivo. Liposome-encapsulated clodronate-mediated elimination of CD8- marginal dendritic cells (DCs) and splenic macrophages (mΦ), but not CD8+ interdigitating DCs, prior to infection resulted in a markedly diminished chemokine and Th1 (IL-2, interferon-γ) cytokine response, although the Th2 response (IL-4) remained relatively intact. Repopulation with marginal DCs and marginal metallophilic macrophages (MMM) restored Th1 cytokine profiles but did not restore chemokine responsiveness or reduce VSV-induced morbidity/mortality. Chemokine competency returned approximately 4 weeks post-depletion, which correlated temporally with repopulation of the spleen with marginal zone macrophages (MZM) and red pulp macrophages (RPM). Unexpectedly, virus-induced morbidity persisted for over 1 month post-depletion and was associated with virus dissemination and distinctive histological lesions in the liver. Depletion of interferon-producing plasmacytoid dendritic cells did not account for virus-induced morbidity because serum levels of type I interferon were not diminished in Cl2MBP-liposomesome- treated mice. Thus, distinct mΦ subsets are critical for chemokine production and viral clearance, and, in their absence, VSV disseminates even in the presence of high titers of interferon.

Original languageEnglish (US)
Pages (from-to)177-189
Number of pages13
JournalVirology
Volume342
Issue number2
DOIs
StatePublished - Nov 25 2005

Bibliographical note

Funding Information:
This work was supported by grants from the National Institutes of Health (AI47800) (RPC), Jeffress Memorial Trust (RPC) and by the Eastern Virginia Medical School Institutional Grant 868030 (RPC).

Keywords

  • Chemokine
  • Cl2MBP-liposome
  • Cytokine
  • Dendritic cell
  • Interferon
  • Splenic macrophage
  • T helper cell
  • Vesicular stomatitis virus

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