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.
View: Text | PDF
Article Virology

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

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

×

Figure 3

Options: View larger image (or click on image) Download as PowerPoint
Cl 13 infection of BMCs in vitro inhibits the generation of CD11c+ DCs. ...
Cl 13 infection of BMCs in vitro inhibits the generation of CD11c+ DCs. (A) Dot plots show CD11c and CD11b expression for uninfected and Cl 13–infected BMCs at days 3, 5, 7, 10, and 11 of culture with GM-CSF. The boxes denote the percentage of CD11c+ DCs in the cultures. Note the reduction in the percentage of CD11c+ cells in Cl 13–infected cultures when compared with uninfected cultures at all timepoints. The data shown are representative of five independent experiments. (B) The percentage of CD11c+ cells as well as the percentage of LCMV-infected CD11c+ cells is plotted for uninfected, ARM-infected, or Cl 13–infected cultures at day 11. Data are represented as the mean ± SD. Statistical differences were determined using a one-way ANOVA (P < 0.05). Asterisks denote a statistical difference from uninfected cultures. (C) The allostimulatory capacity of uninfected, ARM-infected, or Cl 13–infected BM DCs was evaluated at day 11 after culture. Log-serial dilutions (ranging from 102 to 105) of DCs 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 after [3H]thymidine incorporation. (D) Fresh BMCs were isolated from Cl 13– or ARM-infected mice at day 15 after infection and grown for 11 days in the presence of GM-CSF. Dot plots show CD11c and CD11b expression. The boxes denote the percentage of CD11c+ DCs in the cultures.