Viral Targeting of Hematopoietic Progenitors and Inhibition of DC Maturation as a Dual Strategy for Immune Subversion

J Clin Invest. 2004 Mar;113(5):737-45. doi: 10.1172/JCI20243.

Abstract

DCs play a pivotal role in bringing forth innate and adaptive immune responses. Viruses can specifically target DCs, rendering them ineffective in stimulating T cells, which can ultimately lead to immunosuppression. In the present study we have identified several potential mechanisms by which lymphocytic choriomeningitis virus (LCMV) induces immunosuppression in its natural murine host. The immunosuppressive LCMV variant clone 13 (Cl 13) infects DCs and interferes with their maturation and antigen-presenting capacity as evidenced by a significant reduction in the surface expression of MHC class I, MHC class II, CD40, CD80, and CD86 molecules. Additionally, Cl 13 infects hematopoietic progenitor cells both in vivo and in vitro, impairing their development. One mechanism by which hematopoietic progenitors are developmentally impaired is through the Cl 13-induced production of IFN-alpha and IFN-beta (IFN-alpha/beta). Mice deficient in the receptor for IFN-alpha/beta show a normal differentiation of progenitors into DCs despite viral infection. Thus, a virus can evolve a strategy to boost its survival by preventing the maturation of DCs from infected progenitor cells and by reducing the expression of antigen-presenting and costimulatory molecules on developed DCs.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Bone Marrow Cells / cytology
  • CD11c Antigen / biosynthesis
  • CD8 Antigens / biosynthesis
  • Cell Division
  • Dendritic Cells / cytology*
  • Flow Cytometry
  • Hematopoietic Stem Cells / virology*
  • Immunohistochemistry
  • Immunosuppression
  • Lymphocytic choriomeningitis virus / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Confocal
  • Spleen / cytology
  • T-Lymphocytes / metabolism
  • Time Factors

Substances

  • CD11c Antigen
  • CD8 Antigens
  • CD8alpha antigen
  • Membrane Proteins
  • flt3 ligand protein