The Virus-Encoded Chemokine vMIP-II Inhibits Virus-Induced Tc1-Driven Inflammation

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 antigenprimed 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.Because the immune system is composed of single cells, its functional integrity is entirely dependent on the capacity of these cells to traffic, localize, and interact with each other in a timely and precisely controlled manner. Chemokines, capable of activating leukocytes rolling along the endothelium and generating chemotactic gradients in the extracellular space, are key coordinators of these processes. In addition to these physiological roles, it is becoming increasingly evident that chemokines play a crucial role in the pathophysiology of inflammatory and autoimmune diseases (16), and they are regarded as rational targets for the development of anti-inflammatory agents (25).However, antichemokine therapy is hampered by the general redundancy and pleiotropy within the chemokine network (i.e., most chemokines bind more than one receptor, most receptors bind more than one chemokine, and most leukocytes express and respond to more than one chemokine receptor), rendering the chemokine network very robust against intervention (26). Molecules that have the capacity to bind and antagonize multiple types of chemokine receptors could provide a tool to overcome this potential redundancy. Such a protein has evolved in human herpesvirus 8 (HHV-8) and been termed viral macrophage inflammatory protein II (vMIP-II) (27). vMIP-II has been characterized as a functional ...

Efficient T-Cell Surveillance of the CNS Requires Expression of the CXC Chemokine Receptor 3

“…Confirming recent analysis (Frigerio et al, 2002;Lindow et al, 2003;Madsen et al, 2003), both CXCL10 and CCL3 acted as chemoattractants of splenocytes from LCMV-infected WT mice, and flow cytometric analysis revealed that the recruited cells were activated CD8 ϩ T-cells and cells with a low-angle/side scatter pattern consistent with that of mononuclear phagocytes, the two cell types known to dominate in the virus-induced inflammatory exudate (Ceredig et al, 1987;Christensen et al, 1995) (data not shown). In contrast, CCL3, but not CXCL10, induced the migration of cells from LCMV-infected CXCR3-deficient mice.…”

“…Third, mRNA levels for CXCL10 are rapidly upregulated in virus-infected organs, including the CNS (Asensio et al, 1999;Nansen et al, 2000). Fourth, in vitro CXCL10 functions as a chemoattractant of relevant effector cells (i.e., activated CD8 ϩ T-cells and monocyte/macrophages) (Frigerio et al, 2002;Lindow et al, 2003), and this requires expression of CXCR3 (present study). Most important, mice deficient in CXCR3 expression infected intracerebrally with LCMV are relatively resistant to the virus-induced CD8 ϩ T-cell-mediated meningitis, which invariably kills similarly infected WT mice (Fig.…”

“…First, transcript levels for CXCR3 are upregulated in LCMV-infected organs of immunocompetent mice (Lindow et al, 2003). Second, CXCR3 is expressed on antigen-primed CD8 ϩ T-cells, including those generated in the context of viral infection (Fig.…”

“…Transcripts for CXCR3 can be found in inflamed organs of immunocompetent mice infected with LCMV (Lindow et al, 2003). To study the expression of CXCR3 on virus-activated CD8 ϩ T-cells, WT mice were infected intracerebrally with LCMV, and 7 d later, CD8 ϩ T-cells from the spleen and from CSF were analyzed for CXCR3 expression using flow cytometry.…”

“…However, intracerebral inoculation of LCMV leads to infection of the meninges and choroid plexus, and in immunocompetent mice, the result is a severe CD8 ϩ T-cellmediated meningitis that normally kills animals within 7-10 d post infection (dpi) (Ceredig et al, 1987;Doherty et al, 1990;Christensen et al, 1995). Supporting a role for chemokines in LCMV-induced immunopathology, mRNA for both CXCL10 and CXCR3 has been found in the brains of intracerebrally infected mice (Asensio and Campbell, 1997;Nansen et al, 2000;Lindow et al, 2003).…”