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. 2003 Jul;77(13):7393-400.
doi: 10.1128/jvi.77.13.7393-7400.2003.

The virus-encoded chemokine vMIP-II inhibits virus-induced Tc1-driven inflammation

Morten Lindow  1 , Anneline Nansen, Christina Bartholdy, Annette Stryhn, Nils J V Hansen, Thomas P Boesen, Timothy N C Wells, Thue W Schwartz, Allan R Thomsen
Affiliations

The virus-encoded chemokine vMIP-II inhibits virus-induced Tc1-driven inflammation

Morten Lindow et al. J Virol. 2003 Jul.

Abstract

The human herpesvirus 8-encoded protein vMIP-II is a potent in vitro antagonist of many chemokine receptors believed to be associated with attraction of T cells with a type 1 cytokine profile. For the present report we have studied the in vivo potential of this viral chemokine antagonist to inhibit virus-induced T-cell-mediated inflammation. This was done by use of the well-established model system murine lymphocytic choriomeningitis virus infection. Mice were infected in the footpad, and the induced CD8(+) T-cell-dependent inflammation was evaluated in mice subjected to treatment with vMIP-II. We found that inflammation was markedly inhibited in mice treated during the efferent phase of the antiviral immune response. In vitro studies revealed that vMIP-II inhibited chemokine-induced migration of activated CD8(+) T cells, but not T-cell-target cell contact, granule exocytosis, or cytokine release. Consistent with these in vitro findings treatment with vMIP-II inhibited the adoptive transfer of a virus-specific delayed-type hypersensitivity response in vivo, but only when antigen-primed donor cells were transferred via the intravenous route and required to migrate actively, not when the cells were injected directly into the test site. In contrast to the marked inhibition of the effector phase, the presence of vMIP-II during the afferent phase of the immune response did not result in significant suppression of virus-induced inflammation. Taken together, these results indicate that chemokine-induced signals are pivotal in directing antiviral effector cells toward virus-infected organ sites and that vMIP-II is a potent inhibitor of type 1 T-cell-mediated inflammation.

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Figures

FIG. 1.
FIG. 1.
RNase protection assays showing chemokine (A) and chemokine receptor (B) transcription in inflamed LCMV-infected organs. Mice were infected with 200 PFU of LCMV Traub either intracerebrally (for brain samples) or i.v. (for liver and lung samples), and 7 days later (7 days p.i.) organs were harvested from these mice and uninfected controls (uninf.). Total RNA was isolated, and 20 μg was subjected to RNase protection analysis. Each lane represents a single mouse. GAPDH, glyceraldehyde-3-phosphate dehydrogenase.
FIG. 2.
FIG. 2.
Influence of vMIP-II dose on the ability to inhibit LCMV-induced footpad swelling. B6 mice were infected with 200 PFU of LCMV Arm in the right hind footpad, and at the indicated time points half the mice were injected i.v. with vMIP-II or vehicle. Four consecutive injections of 5 μg did not affect inflammation (A), while 20 μg markedly delayed and attenuated the swelling (B). Values represent medians and ranges of five animals. *, P < 0.05.
FIG. 3.
FIG. 3.
Effect of vMIP-II treatment on footpad swelling and antigen-specific T-cell frequencies following treatment during different phases of the immune response. Mice were infected with 200 PFU of LCMV Arm in the footpads and treated with i.v. injections of 20 μg of vMIP-II either early (days 0.5, 1, 1.5, and 2 p.i.), late (days 5.5, 6, 6.5, and 7 p.i.), or not at all (control). (A) LCMV-induced footpad swelling; values represent medians and ranges of five animals from one representative experiment. *, P < 0.05. (B) Frequency of LCMV-specific T cells. On day 9 p.i., mice were sacrificed, and splenocytes were stimulated with either of two immunodominant LCMV epitopes (GP33-41 and NP396-404). After 5 h of stimulation cells were stained for CD8, permeabilized, and stained for IFN-γ intracellularly. Points represent frequencies for individual animals; gates have been set for CD8+ cells. Without peptide stimulation <0.2% of the cells stained positive for IFN-γ.
FIG. 4.
FIG. 4.
vMIP-II inhibits chemokine-induced in vitro migration of virus-activated CD8+ T cells. Splenocytes from mice infected with 200 PFU of LCMV Traub 7 days earlier were incubated with or without vMIP-II for 1 h and then allowed to migrate toward IP-10 for 3 h in a double-chamber assay. The percentages of CD8+ VLA-4high cells that have migrated into the lower, chemokine-containing chamber are presented. Averages ± SDs are presented.
FIG. 5.
FIG. 5.
vMIP-II does not inhibit target cell lysis or chemokine production-release in vitro. Splenocytes from mice infected with 200 PFU of LCMV Traub 8 days earlier were incubated with peptide-coated (GP33-41 or NP396-404) or uncoated target cells for 6 h in the presence or absence of vMIP-II (upper panel). Alternatively, splenocytes were incubated with these peptides (0.1 μg/ml) for 6 h and the level of chemokine released into the supernatant was determined (lower panel); if no peptide was added, <100 pg/ml was produced (indicated by stippled lines). Averages (± SDs) are presented; for the cytotoxicity assay SDs were too small to be readily depicted.
FIG. 6.
FIG. 6.
Influence of vMIP-II treatment on adoptively transferred DTH. Recipient mice were infected with 2 × 106 PFU of LCMV Traub in the footpad 4 h before adoptive transfer of day 8 virus-primed, adherent cell-depleted splenocytes. Either cells were transplanted i.v. and recipients were treated i.v. (A), or cells and treatment were administered at the site of viral challenge (B). Values represent medians and ranges of five animals. *, P < 0.05.
FIG. 7.
FIG. 7.
Influence of Met-RANTES treatment on adoptively transferred DTH in wild-type B6 mice (A) or CCR5−/− mice (B). Values represent medians and ranges of five animals; open symbols represent untreated mice, while closed symbols represent Met-RANTES-treated animals.
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References

    1. Andersson, E. C., J. P. Christensen, O. Marker, and A. R. Thomsen. 1994. Changes in cell adhesion molecule expression on T cells associated with systemic virus infection. J. Immunol. 152:1237-1245. - PubMed
    1. Andreasen, S. O., J. E. Christensen, O. Marker, and A. R. Thomsen. 2000. Role of CD40 ligand and CD28 in induction and maintenance of antiviral CD8+ effector T cell responses. J. Immunol. 164:3689-3697. - PubMed
    1. Andreasen, S. O., J. P. Christensen, O. Marker, and A. R. Thomsen. 1999. Virus-induced non-specific signals cause cell cycle progression of primed CD8+ T cells but do not induce cell differentiation. Int. Immunol. 11:1463-1473. - PubMed
    1. Asensio, V. C., and I. L. Campbell. 1997. Chemokine gene expression in the brains of mice with lymphocytic choriomeningitis. J. Virol. 71:7832-7840. - PMC - PubMed
    1. Boshoff, C., Y. Endo, P. D. Collins, Y. Takeuchi, J. D. Reeves, V. L. Schweickart, M. A. Siani, T. Sasaki, T. J. Williams, P. W. Gray, P. S. Moore, Y. Chang, and R. A. Weiss. 1997. Angiogenic and HIV-inhibitory functions of KSHV-encoded chemokines. Science 278:290-294. - PubMed

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