Bystander activation of CD4(+) T cells accounts for herpetic ocular lesions

PURPOSE. Stromal keratitis is an immunopathologic consequence of herpes sim plex virus (HSV) infection of the cornea. The lesion is immunopathologic, b ut the identities of molecules that drive the reaction remain unresolved. T o exclude viral antigen recognition as a necessary step in the disease proc ess, ocular HSV infection was followed in Tg-RAG mice (OVA-TCR transgenic m ice crossed to RAG2-deficient mice) whose limited T-cell repertoire did not include immune responsiveness to HSV. METHODS. Mice with T-cell specificity to OVA peptide (Tg-RAG mice) as well as control DO11.10 and BALB/c mice were infected with HSV on the scarified cornea and subjected to clinical, histologic, and immunologic analysis. To evaluate involvement of OVA-specific CD4(+) T cells in lesion development i n Tg-RAG mice, monoclonal antibody to CD4(+) T cells was used for in vivo C D4(+) T-cell depletion. RESULTS. Tg-RAG mice were capable of eliciting ocular lesions in the absenc e of detectable reactivity to viral antigens. Lesion manifestation in Tg-RA G mice mas CD4(+) T-cell dependent and the cellular infiltrates and their i nflammatory products in the HSV-infected cornea were comparable to similarl y infected BALB/c and DO11.10 mice. CONCLUSIONS. The authors conclude that mechanisms other than viral antigen recognition, and hence molecular mimicry, are at play and are sufficient to cause HSV-induced stromal keratitis. The data imply a significant role for non-virus-specific CD4(+) T cells that could become activated by an inflam matory milieu consisting of enhanced accessory molecules and proinflammator y cytokines in the cornea.