A Central Role for CD4⁺T Cells and RANTES in Virus-Induced Central Nervous System Inflammation and Demyelination

Abstract

Infection of C57BL/6 mice with mouse hepatitis virus (MHV) results in a demyelinating encephalomyelitis characterized by mononuclear cell infiltration and white matter destruction similar to the pathology of the human demyelinating disease multiple sclerosis. The contributions of CD4 ؉ and CD8 ؉ T cells in the pathogenesis of the disease were investigated. Significantly less severe inflammation and demyelination were observed in CD4؊/؊ mice than in CD8 ؊/؊ and C57BL/6 mice (P < 0.002 and P < 0.001, respectively). Immunophenotyping of central nervous system (CNS) infiltrates revealed that CD4؊/؊ mice had a significant reduction in numbers of activated macrophages/microglial cells in the brain compared to the numbers in CD8 ؊/؊ and C57BL/6 mice, indicating a role for these cells in myelin destruction. Furthermore, CD4 ؊/؊ mice displayed lower levels of RANTES (a C-C chemokine) mRNA transcripts and protein, suggesting a role for this molecule in the pathogenesis of MHV-induced neurologic disease. Administration of RANTES antisera to MHV-infected C57BL/6 mice resulted in a significant reduction in macrophage infiltration and demyelination (P < 0.001) compared to those in control mice. These data indicate that CD4 ؉ T cells have a pivotal role in accelerating CNS inflammation and demyelination within infected mice, possibly by regulating RANTES expression, which in turn coordinates the trafficking of macrophages into the CNS, leading to myelin destruction.Demyelination is a complex neuropathological process in which the myelin sheath that insulates and protects axons is damaged or destroyed. Several animal models of demyelination have been developed that have provided valuable contributions to the understanding of the immunopathological events that may drive human demyelinating diseases such as multiple sclerosis (MS) (22,31). Among these is the neurotropic mouse hepatitis virus (MHV) model of virus-induced demyelination (12,18). MHV is a positive-strand RNA virus that causes a variety of clinical diseases in susceptible strains of mice (23). Neurovirulent strains of MHV cause an acute encephalomyelitis that may ultimately progress to demyelinating disease characterized clinically by abnormal gait and hind-limb paralysis. Histologically, affected animals exhibit mononuclear cell infiltration and myelin destruction. Early studies suggested that the demyelination observed in MHV-infected mice was the result of virus-induced damage or destruction of oligodendrocytes (9, 36). However, more recent reports have indicated that MHV-induced demyelination is more complex and may also involve immunopathologic responses against viral antigens expressed in infected tissues (5, 35).As T cells are considered central to the development of demyelinating lesions in animal models of demyelination as well as MS, it is imperative to better understand the mechanisms by which these cells exert their pathological effect (24, 25). We sought to evaluate the contributions of CD4 ϩ and CD8 ϩ T cells in MHV-induced central nervous system (CNS) d...

Differential roles for CXCR3 in CD4+ and CD8+ T cell trafficking following viral infection of the CNS

“…The marked reduction in CD4 + T cell infiltration following either CXCL10 or CXCR3 neutralization correlates with an arrest in demyelination. These data support previous studies indicating an important role for CD4 + T cells in amplifying the severity of demyelination in MHV-infected mice [14,15]. Although we previously reported an important role for CCL5 in enhancing demyelination through recruitment of macrophages into the CNS of MHV-infected C57BL/6 mice, demyelination is inhibited in BALB/c mice even in the presence of CCL5 (Fig.…”

“…Mice that survive the acute stage of CNS MHV infection develop a demyelinating disease characterized by persistent viral RNA and antigen within white matter tracts accompanied by mononuclear cell infiltration and myelin destruction [9,14,[25][26][27][28]. Previous work demonstrating that chronic CXCL10 expression amplifies the severity of demyelination in MHV-infected mice led to the hypothesis that CXCR3 is similarly involved during chronic neurologic disease, allowing activated T cells to accumulate within the CNS in response to CXCL10 [19].…”

“…5B). Previous studies have indicated that T cell secretion of the macrophage chemoattractant CCL5 can contribute to demyelination [14,22]. Therefore, CCL5 expression and macrophage accumulation within the CNS were evaluated following CXCR3 neutralization.…”

“…Following viral clearance, viral RNA persists, resulting in a chronic demyelinating disease that is both clinically and histologically similar to the human demyelinating disease multiple sclerosis (MS) [9][10][11][12][13]. Numerous studies support the notion that immunopathologic responses to viral antigens expressed in infected tissues are the primary mechanisms contributing to MHVinduced demyelination [14][15][16][17]. MHV infection of immunosuppressed or immunodeficient mice results in high viral titers and death, while demyelination is undetectable [15,16].…”

“…During both acute and chronic MHV infection, chemokines and chemokine receptors are expressed within the CNS, influencing host defense as well as disease by regulating inflammation within the CNS [9,14,[18][19][20][21][22][23]. Studies from our laboratory have clearly demonstrated important roles for CXCR3 ligands during both acute and chronic MHV infection of C57BL/6 mice [18,19,23].…”