Role of Stat4-Mediated Signal Transduction Events in the Generation of Aggressor CD4 + T Cells in Herpetic Stromal Keratitis Pathogenesis

Ocular infection with herpes simplex virus (HSV) causes a vision-impairing inflammatory reaction called herpetic stromal keratitis. In murine models, herpetic stromal keratitis lesions appear to be immunopathologic, mediated by CD4⁺ T cells of Th1 phenotype. To provide insight about cytokine networks and signaling events involved in the development of aggressor CD4⁺ T cells, ocular HSV infection was followed in mice deficient in Stat4 (Stat4^−/− mice), the signal transducer for the cytokine interleukin-12 (IL-12). After ocular HSV infection of Stat4^−/− and control BALB/c mice, clinical, histologic, and immunologic analyses were carried out. Further, to evaluate the involvement of Stat4 in the development of this aggressor population, naive CD4⁺ T cells from Stat4^−/− and BALB/c mice were adoptively transferred to C.B-17 SCID mice 1 day after corneal infection. Although Stat4^−/− mice demonstrated increased susceptibility to lethal encephalitis and facial lesions, interestingly, these mice had less severe stromal keratitis in comparison to control animals. Adoptive transfer of naive CD4⁺ T cells from Stat4^−/− mice failed to produce disease in infected SCID recipients. The data imply a significant role of Stat4-mediated signaling events in the generation of an aggressor CD4⁺ T cell population in stromal keratitis pathogenesis.