Bystander Activation Involving T Lymphocytes in Herpetic Stromal Keratitis

Abstract

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 present study demonstrates that lesion expression in such mice depends on continuous viral replication, whereas in immunocompetent mice, lesions occurred even if virus replication was terminated at 4 days after infection. The continuous replication in TgSCID mice was considered necessary to produce an activating stimulus to CD4+ T cells that invade the cornea. Lesions in TgSCID were resistant to control by cyclosporin A, but were inhibited by treatment with rapamycin. This result was interpreted to indicate that T cell activation involved a non-TCR-mediated cytokine-driven bystander mechanism. Bystander activation was also shown to play a role in HSK lesions in immunocompetent mice. Accordingly, in immunocompetent DO11.10 mice, lesions were dominated by KJ1.26+ OVA-specific CD4+ T cells that were unreactive with HSV. In addition, KJ1.26+ HSV nonimmune cells parked in ocularly infected BALB/c mice were demonstrable in HSK lesions. These results provide insight for the choice of new strategies to manage HSK, an important cause of human blindness.

Selective retention of herpes simplex virus-specific T cells in latently infected human trigeminal ganglia

“…Intralesional accumulation of activated nonspecific T cells, referred to as bystander T cells, has been reported in other localized viral infections of the brain in mouse models (37)(38)(39). With regard to HSV-1, the immunopathogenicity of corneal tissue-infiltrating bystander T cells has been shown in the mouse model of herpetic stromal keratitis (40,41). It was postulated that HSV-1 infection of the cornea induced a local environment in which expressed cytokines and chemokines attract and activate cornea-infiltrating T cells directly, rather than by TCR-mediated signaling (41).…”

Bystander stimulation of activated CD4+ T cells of unrelated specificity following a booster vaccination with tetanus toxoid

“…However, it has been shown that chronic parasitic infection (Leishmania donovani), associated with a strong inflammatory response, induces expansion of heterologous CD4 1 memory T cells [6]. In a model of herpetic stromal keratitis, a chronic inflammatory reaction in the corneal stroma, which follows ocular infection with herpes simplex virus, a nonantigen-specific bystander activation of CD4 1 T cells appears to account for the immunopathological lesions [7,8]. Information in human subjects is even more limited, although anecdotal observations of parallel expansions of CD4 1 T cells against tetanus toxoid (TT) during infection with influenza virus have been reported previously [9].…”

Blocking 4-1BB/4-1BB Ligand Interactions Prevents Herpetic Stromal Keratitis

“…In corneas of BALB/c mice infected with the RE strain of HSV-1, Russell et al (2) showed that HSK resulted from CD4 ϩ T cells secreting IFN-␥, IL-12, and other lymphokines typically produced by Th1 cells. Deshpande et al (3,4) showed that activated CD4 ϩ T cells were required for the development of HSK, which occurred as a non-TCR-mediated event. On the basis of these studies, the authors proposed a bystander activation model of HSK.…”