CXC Chemokine Ligand 10 Controls Viral Infection in the Central Nervous System: Evidence for a Role in Innate Immune Response through Recruitment and Activation of Natural Killer Cells

Abstract

The CXC chemokine ligand 10 (CXCL10) is a non-ELR CXC chemokine that exerts a potent chemotactic effect on activated T cells through binding the receptor CXCR3 (5). CXCL10 is expressed within tissues following viral infection, suggesting an important role for this chemokine in host defense by contributing to lymphocyte activation, extravasation, and accumulation of virus-specific T cells within sites of infection. Indeed, recent studies with antibody-mediated targeting of CXCL10 and CXCL10 Ϫ/Ϫ mice demonstrated that the absence of CXCL10 function results in increased mortality accompanied by increased viral titers and reduced T-cell infiltration within the brains of mice infected intracerebrally with a murine coronavirus (mouse hepatitis virus [MHV]) (8,20). In addition, CXCL10 expression modulates the pathogenesis of liver disease in adenovirus-infected mice and transgenic mice capable of replicating hepatitis B virus by attracting CD8 ϩ T lymphocytes into the liver (2, 11).These studies indicate that CXCL10 functions as a sentinel molecule in host defense and is important in the development of a protective T-cell response following viral infection. Recent findings have also illustrated an important role for chemokines in innate defense following viral infection. For example, in addition to its chemotactic effect on T cells, CXCL10 has also been shown to induce natural killer (NK) cell migration following viral infection (2, 11, 22, 23). Expression of both CXCL10 and CXC chemokine ligand 9 (CXCL9) has been found to contribute to antiviral immune responses in the absence of T and B cells (24). Although these chemokines have a demonstrated direct antimicrobial effect (6), their protective effect following vaccinia virus infection was a result of enhanced NK cell trafficking and activation (24).Our laboratory is interested in the functional contributions of chemokines and chemokine receptors in both host defense and disease progression within the context of coronavirus infection of the central nervous system (CNS). Intracerebral infection of susceptible strains of mice with MHV results in an acute encephalomyelitis followed by a chronic immune-mediated demyelinating disease that is similar in pathology to the human demyelinating disease multiple sclerosis (16). A robust expression of chemokine genes occurs within the CNS following MHV infection that precedes and accompanies leukocyte entry (18).Although NK cells can be readily detected within the CNS early following MHV infection, their precise contributions to antiviral immune responses within the CNS have not been well established. Furthermore, CXCL10 is prominently expressed as early as day 1 postinfection, suggesting that this molecule may function in enhancing innate immune responses by attracting NK cells into the CNS. Therefore, to further understand the relationship between CXCL10 and the innate immune response to viral infection of the CNS, we constructed a recombinant MHV capable of expressing mouse CXCL10. Intracerebral infection of RAG1 Ϫ/Ϫ mice with t...

Antibody Targeting of the CC Chemokine Ligand 5 Results in Diminished Leukocyte Infiltration into the Central Nervous System and Reduced Neurologic Disease in a Viral Model of Multiple Sclerosis

“…MHV infection of astrocytes results in robust expression of CXCL10 that is most likely controlled by type I IFN expression and not by cytokines and/or chemokines derived from infiltrating T cells such as IFN-␥ and CCL5, respectively. Moreover, MHV infection of the CNS of RAG1 Ϫ/Ϫ mice (lacking T and B cells) results in robust expression of CXCL10 by astrocytes, which further supports the fact that expression of this chemokine is not dependent on factors generated from infiltrating T cells (52).…”

CD4+ T cell migration into the cornea is reduced in CXCL9 deficient but not CXCL10 deficient mice following herpes simplex virus type 1 infection

“…Previous studies have reported positive [15,16] and negative [17,18] consequences linked to CXCL10 or CXCR3 expression during infection or autoimmune disease implying the role of CXCR3 and its ligands may be tissue-and pathogen-specific.…”

NK Cells in Central Nervous System Disorders

“…In pathological conditions, the integrity of the BBB and the BCSFB can be disturbed, becoming permissive for the entry of inflammatory cells. Among them, NK cells were shown to be recruited to the CNS following several pathological conditions (2)(3)(4)(5)(6).…”

“…Nonetheless, their mode of entry into CNS and the molecules leading to this recruitment are poorly understood. This recruitment could be coordinated by CNS resident cells, such as microglia, astrocytes, and neurons, that secrete chemokines involved in NK cell migration, such as CCL2, CXCL10, and CX3CL1 (3,18,38) .…”