Role of Dendritic Cells in Differential Susceptibility to Viral Demyelinating Disease

Abstract

Although persistent viral diseases are a global health concern, the mechanisms of differential susceptibility to such infections among individuals are unknown. Here, we report that differential interactions between dendritic cells (DCs) and virus are critical in determining resistance versus susceptibility in the Theiler murine encephalomyelitis virus–induced demyelinating disease model of multiple sclerosis. This virus induces a chronic demyelinating disease in susceptible mice, whereas the virus is completely cleared in resistant strains of mice. DCs from susceptible mice are more permissive to viral infection, resulting in severe deficiencies in development, expansion, and function, in contrast to DCs from resistant mice. Although protective prior to viral infection, higher levels of type I interferons (IFNs) and IFN-γ produced by virus-infected DCs from susceptible mice further contribute to the differential inhibition of DC development and function. An increased DC number and/or acquired resistance of DCs to viral infection render susceptible mice resistant to viral persistence and disease progression. Thus, the differential permissiveness of DCs to infectious agents and its subsequent functional and developmental deficiencies determine the outcome of infection- associated diseases. Therefore, arming DCs against viral infection–induced functional decline may provide a useful intervention for chronic infection-associated diseases.

Predominant Clonal Accumulation of CD8+T Cells with Moderate Avidity in the Central Nervous Systems of Theiler's Virus-Infected C57BL/6 Mice

“…However, the levels of IFN-␥ production were similar in the presence or absence of added DCs across different concentrations of the cognate peptide (data not shown). The lack of significant deficiencies in the CNS APCs from virus-infected resistant B6 mice is consistent with our previous observation (20). Therefore, it is very unlikely that the differences in functional avidity presented in Fig.…”

Anticapsid Immunity Level, Not Viral Persistence Level, Correlates with the Progression of Theiler's Virus-Induced Demyelinating Disease in Viral P1-Transgenic Mice

“…In addition, we have previously demonstrated that antigen-presenting cells (macrophages and dendritic cells) as well as microglia from susceptible SJL mice produce higher levels of type I IFNs, yet the viral replication levels are severalfold higher than those from resistant B6 mice (17,18). These results indicate that TMEV BeAn infection strongly induces type I IFNs in the presence of L protein and that viral replication is not interrupted in cells producing type I IFNs.…”

“…In general, highaffinity CD8 ϩ T cells are preferentially tolerized by deletion or anergy in vivo. In fact, the relative levels of IFN-␥-producing cells upon stimulation with serial 10-fold-decreased epitope peptide concentrations indicated that functional avidity to the dominant epitope (VP3 159-166 ) is 50-and 100-fold higher than those to the subdominant epitopes (VP3 173-181 and VP1 [11][12][13][14][15][16][17][18][19][20] , respectively) (data not shown). These results are consistent with the preferential reduction of high-affinity VP3 159-166 -specific CD8 ϩ T cells over low-affinity subdominant epitope-reactive CD8 ϩ T cells.…”

“…ϩ T-cell levels specific for the predominant epitope, VP3 159-166 , were significantly reduced in SJL P1-Tg mice, although CD8 ϩ T-cell levels specific for subdominant epitopes (VP3 173-181 and VP1 [11][12][13][14][15][16][17][18][19][20] were largely unaffected throughout the course of infection (Fig. 5).…”

Infiltrating Macrophages Are Key to the Development of Seizures following Virus Infection

“…TMEV infects a variety of cells both in the CNS and in the periphery, including macrophages, dendritic cells, microglia, and astrocytes (9)(10)(11)(12). Infection of cells with TMEV triggers a proinflammatory response consisting of type I interferons, tumor necrosis factor alpha (TNF-␣), interleukin-6 (IL)-6, and various chemokines (13)(14)(15)(16)(17)(18).…”