Evidence that precursor cytotoxic T cells mediate acute necrosis in HSV-1-infected retinas

Following uniocular anterior chamber injection of HSV-1 (KOS) in BALB/c and A/J mice, it is paradoxical that (a) acute retinal necrosis (ARN) develops only in the uninjected eyes, and (b) ARN occurs only in mice that are immunocompetent, event though these mice invariably display anterior chamber associated immune deviation (ACAID), wherein delayed hypersensitivity to HSV antigens is grossly impaired. Previous studies have revealed that ARN develops only if the titer of infectious virus in the contralateral eye exceeds 4 Log10 PFU, indicating that virus infection is essential to ARN. However, HSV-1 titers in contralateral eyes of similarly infected athymic mice also exceed 4 Log10 PFU, even though these mice never develop ARN - implying that virus alone is insufficient to cause retinal cell destruction. In an effort to define the pathogenic immune component of ARN, we have evaluated in vitro viral antigen-specific T cell responses in mice with ARN and ACAID. We found that T cells, harvested from draining ipsilateral cervical lymph nodes and contrateral eye proliferate in response to viral antigens, express IL-2 receptors, and include HSV-1-specific precursor cytotoxic T cells (pTc), but not direct cytotoxic T cells (Tc). Since the time of appearance of HSV-specific pTc in the contralateral eye coincides with entry of infectious virus into that eye, and since their mutual appearance heralds the onset of retinal necrosis, we conclude that destruction of the retina is initiated by virus-specific cytotoxic T cells that lyse HSV-infected retinal cells.