Protective and Pathological Roles of Virus-Specific and Bystander CD8+ T Cells in Herpetic Stromal Keratitis

Abstract

Herpetic stromal keratitis (HSK), resulting from corneal HSV-1 infection, represents a T cell-mediated immunopathologic lesion. In T cell transgenic mice on a SCID or RAG knockout background, the T cells mediating lesions are unreactive to viral Ags. In these bystander models, animals develop ocular lesions but are unable to control infection. Transfer of HSV-immune cells into a CD8+ T cell bystander model resulted in clearance of virus from eyes, animals survived, and lesions developed to greater severity. However, the adoptively transferred CD8+ T cells were not evident in lesions, although they were readily detectable in the lymphoid tissues as well as in the peripheral and CNS. Our results indicate that viral-induced tissue damage can be caused by bystander cells, but these fail to control infection. Immune CD8+ T cells trigger clearance of virus from the eye, but this appears to result by the T cells acting at sites distal to the cornea. A case is made that CD8+ T cell control is expressed in the trigeminal ganglion, serving to curtail a source of virus to the cornea.

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).…”

“…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). We hypothesize that the majority of the T cells residing in human TG, which do not contain a blood-brain barrier similar to the CNS (42), have entered the TG mainly because of their activation status acquired outside the TG and accumulate and differentiate into late effector memory T cells by nonspecific stimulation within the TG by cytokines, including IL-6 and IL-15 (7,43,44), and chemokines, such as RANTES, expressed locally in response to a latent viral infection (7,8).…”

Latent Infection with Herpes Simplex Virus Is Associated with Ongoing CD8+T-Cell Stimulation by Parenchymal Cells within Sensory Ganglia

“…However, interferon-␣/␤ can partially activate T cells in an antigen-independent manner resulting in CD69 expression (53), which could explain its presence on bystander cells during HSV latency. Also of interest in the context of HSV, other researchers have proposed that the pathology associated with herpetic stromal keratitis can be induced by infiltrating bystander transgenic T cells (4,17), presumably as a result of some form of nonspecific activation within the eye that may be analogous to what is seen here in the infected ganglia.…”

Altered lymphopoiesis and immunodeficiency in miR-142 null mice

“…C57BL/6 mice are normally resistant to ocular HSV-1 infection and depend on a robust T cell response to the virus for protection. [19][20][21][22] However, miR-142 2/2 mice were highly susceptible to infection with HSV-1 and died of virus-induced encephalitis within 11 days ( Figure 5D). Lowering the titer of HSV-1 by ;30-fold did not improve the survival of miR-142 2/2 mice.…”