Bystander activation involving T lymphocytes in herpetic stromal keratitis

Herpes simplex virus infection of mouse corneas can lead to the development of an immunopathological lesion, termed herpetic stromal keratitis (HSK). Such lesions also occur in TCR-transgenic mice backcrossed to SCID (TgSCID) that are unable to mount detectable HSV-specific immune responses. The pre sent study demonstrates that lesion expression in such mice depends on cont inuous viral replication, whereas in immunocompetent mice, lesions occurred even if virus replication was terminated at 4 days after infection. The co ntinuous replication in TgSCID mice was considered necessary to produce an activating stimulus to CD4(+) T cells that invade the cornea. Lesions in Tg SCID were resistant to control by cyclosporin A, but were inhibited by trea tment with rapamycin. This result was interpreted to indicate that T cell a ctivation involved a non-TCR-mediated cytokine-driven bystander mechanism. Bystander activation was also shown to play a role in HSK lesions in immuno competent mice. Accordingly, in immunocompetent DO11.10 mice, lesions were dominated by KJ1.26(+) OVA-specific CD4(+) T cells that were unreactive wit h HSV. In addition, KJ1.26(+) HSV nonimmune cells parked in ocularly infect ed BALB/c mice were demonstrable in FISK lesions. These results provide ins ight for the choice of new strategies to manage HSK, an important cause of human blindness.