We examined the extent to which CXCR3 mediates resistance to dengue infection. Following intracerebral infection with dengue virus, CXCR3-deficient (CXCR3−/−) mice showed significantly higher mortality rates than wild-type (WT) mice; moreover, surviving CXCR3−/− mice, but not WT mice, often developed severe hind-limb paralysis. The brains of CXCR3−/− mice showed higher viral loads than those of WT mice, and quantitative analysis using real-time PCR, flow cytometry, and immunohistochemistry revealed fewer T cells, CD8+ T cells in particular, in the brains of CXCR3−/− mice. This suggests that recruitment of effector T cells to sites of dengue infection was diminished in CXCR3−/− mice, which impaired elimination of the virus from the brain and thus increased the likelihood of paralysis and/or death. These results indicate that CXCR3 plays a protective rather than an immunopathological role in dengue virus infection. In studies to identify critical CXCR3 ligands, CXCL10/IFN-inducible protein 10-deficient (CXCL10/IP-10−/−) mice infected with dengue virus showed a higher mortality rate than that of the CXCR3−/− mice. Although CXCL10/IP-10, CXCL9/monokine induced by IFN-γ, and CXCL11/IFN-inducible T cell α chemoattractant share a single receptor and all three of these chemokines are induced by dengue virus infection, the latter two could not compensate for the absence of CXCL10/IP-10 in this in vivo model. Our results suggest that both CXCR3 and CXCL10/IP-10 contribute to resistance against primary dengue virus infection and that chemokines that are indistinguishable in in vitro assays differ in their activities in vivo.

Using a model of 2,4-dinitro-1-fluorobenzene-induced contact hypersensitivity (CHS) we found that, as compared with wild-type mice, IL-15 receptor a chain (IL-15Ra)-deficient mice showed significantly less ear swelling. This decreased response was associated with diminished expression of CCL5/RANTES and CXCL10/IP-10, chemokines critical for effector cell recruitment, in the inflamed tissue. We determined that both the number of CD8 + T cells infiltrating the affected skin and the production of CCL5/RANTES by antigen-stimulated CD8 + T cells were decreased in IL-15Ra -/-mice. The lower levels of CXCL10/IP-10 suggested that the IL-15Ra -/-mice had reduced production of IFN-c, the primary inducer of CXCL10/IP-10, which was in fact the case. However, by contrast with CCL5/RANTES, the diminished levels of IFN-c were likely due to the decreased number of skin-infiltrating CD8 + T cells, since IFN-c production by antigen-stimulated CD8 + T cells was comparable between wild-type and IL-15Ra -/-mice. Our data suggest a positive, pro-inflammatory feedback loop involving CCL5/ RANTES, IFN-c and CXCL10/IP-10 that underlies the CHS reaction and that is disrupted, likely primarily by a defect in CCL5/RANTES production, in mice lacking IL-15Ra, resulting in impaired leukocyte recruitment and inflammation. Moreover, it is particularly noteworthy that the defect in CCL5/RANTES expression in CD8 + T cells is intrinsic to the absence of IL-15Ra, indicating that IL-15Ra is critical for CCL5/ RANTES expression in CD8 + T cells.