Viral targeting of hematopoietic progenitors and inhibition of DC maturation as a dual strategy for immune subversion
Noemí Sevilla, Dorian B. McGavern, Chao Teng, Stefan Kunz, Michael B.A. Oldstone
Noemí Sevilla, Dorian B. McGavern, Chao Teng, Stefan Kunz, Michael B.A. Oldstone
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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

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IFN-α/βR0/0 mice infected with Cl 13 expand DCs in response to Flt3-L tr...
IFN-α/βR0/0 mice infected with Cl 13 expand DCs in response to Flt3-L treatment. Splenic DCs were isolated from uninfected or Cl 13–infected IFN-α/βR0/0 and 129/SvEv mice treated for 10 days with Flt3-L (see Figure 3). The Flt3-L treatment was initiated at day 15 after infection. (A) Dot plots show CD11c+CD8α+ and CD11c+CD8α– DCs in mice treated with PBS or Flt3-L. Boxes denote the percentage of CD11c+CD8α+ DCs. Note the normal expansion of CD11c+CD8α+ DCs in Flt3-L–treated IFN-α/βR0/0 mice infected with Cl 13. (B) The fold expansion of both CD11c+CD8α+ and CD11c+CD8α– DCs is plotted for naive and Cl 13–infected mice. The fold expansion was calculated by dividing the absolute number of each DC subset in Flt3-L–treated mice by the absolute number of cells in PBS-treated mice. Data are presented as the mean ± SD. Statistical differences denoted by asterisks were determined using a Student t test (P < 0.05).