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Viral targeting of hematopoietic progenitors and inhibition of DC maturation as a dual strategy for immune subversion
Noemí Sevilla, … , Stefan Kunz, Michael B.A. Oldstone
Noemí Sevilla, … , Stefan Kunz, Michael B.A. Oldstone
Published March 1, 2004
Citation Information: J Clin Invest. 2004;113(5):737-745. https://doi.org/10.1172/JCI20243.
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Article Virology

Viral targeting of hematopoietic progenitors and inhibition of DC maturation as a dual strategy for immune subversion

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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-α and IFN-β (IFN-α/β). Mice deficient in the receptor for IFN-α/β 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.

Authors

Noemí Sevilla, Dorian B. McGavern, Chao Teng, Stefan Kunz, Michael B.A. Oldstone

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Figure 1

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LCMV Cl 13 infection reduces the expression of cell surface molecules on...
LCMV Cl 13 infection reduces the expression of cell surface molecules on splenic DCs. Labeling with anti-CD11c and -CD80 antibodies was used to distinguish between CD11c+CD8α+ and CD11c+CD8α– DCs. (A) Histograms show one of four representative experiments analyzing the expression of cell surface molecules on CD11c+CD8α+ and CD11c+CD8α– spleen DCs from Cl 13– or ARM-infected mice at day 15 after infection. Dotted histograms indicate background staining with isotype control antibodies, white histograms represent ARM-infected mice, and shaded histograms represent Cl 13–infected mice. (B) The RFI of surface molecules expressed on CD11c+CD8α+ splenic DCs from day 3 to day 360 after infection is displayed. Each bar represents the RFI of a given surface molecule on CD11c+CD8α+ spleen DCs. The RFI was calculated as indicated in Methods. Data are presented as mean ± SD. Asterisks denote a statistically significant reduction in Cl 13–infected mice compared with ARM-infected mice (Student t test, P < 0.05). (C) Viral load in serum of 5–8 Cl 13–infected mice analyzed from day 3 to day 120 after infection as determined by plaque assay. Each filled circle represents an individual mouse. The line at each timepoint represents the mean of all mice in each group. (D) The allostimulatory capacity of DCs from the spleens of either uninfected (white bars), ARM-infected (gray bars), or Cl 13–infected (black bars) mice is indicated at different timepoints after infection. DCs from infected or uninfected C57BL/6 (H-2b) mice were irradiated and used as stimulator cells for allogeneic T cells from BALB/c (H-2d) mice at a T cell/DC ratio of 5:1 in the MLR. Proliferation was measured in cpm (average cpm ± SD) after [3H]thymidine incorporation. Each bar represents the average of at least four mice.

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