MHC II-restricted, CD4+ cytotoxic T lymphocytes specific for herpes simplex virus-1: implications for the development of herpetic stromal keratitis in mice

Herpetic stromal keratitis (HSK) appears to represent an immunopathological reaction in which CD4+ T cells play a prominent role. However, the exact immunopathological mechanism(s) utilized by CD4+ T cells during HSK remains to be elucidated. In this study, the presence of cytotoxic CD4+ T lymphocytes in the cervical and retropharyngeal lymph nodes of Balb/c mice experiencing HSK was investigated. After in vitro depletion of CD4+ or CD8+ T cells with specific monoclonal antibodies and complement treatment, the cytotoxic functions of the remaining T cell populations were assayed by using target cells expressing either MHC Class I or both Class I and Class II. Our results showed the presence of a distinct cytotoxic T lymphocyte (CTL) population which was CD4+ and demonstrated lytic activity in a Class II-restricted fashion. Furthermore, these cells were able to develop into efficient effector CTL in the absence of CD8+ T lymphocytes as assessed by in vivo depletion experiments. Immunohistochemical methods were also utilized to show the presence of both CD4+ lymphocytes and I-A+ cells in the corneal tissues during HSK. These findings support the notion that direct lysis of infected Class II-bearing corneal cells by CD4+ CTL might be one of the mechanisms leading to stromal immunopathology in herpetic infections.