Bystander activation of CD4+ T cells accounts for herpetic ocular lesions.
OBJECTIVE
Stromal keratitis is an immunopathologic consequence of herpes simplex virus (HSV) infection of the cornea. The lesion is immunopathologic, but the identities of molecules that drive the reaction remain unresolved. To exclude viral antigen recognition as a necessary step in the disease process, ocular HSV infection was followed in Tg-RAG mice (OVA-TCR transgenic mice 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 in Tg-RAG mice, monoclonal antibody to CD4+ T cells was used for in vivo CD4+ T-cell depletion.


RESULTS
Tg-RAG mice were capable of eliciting ocular lesions in the absence of detectable reactivity to viral antigens. Lesion manifestation in Tg-RAG mice was CD4+ T-cell dependent and the cellular infiltrates and their inflammatory products in the HSV-infected cornea were comparable to similarly 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 inflammatory milieu consisting of enhanced accessory molecules and proinflammatory cytokines in the cornea.
Gangappa
S
S
Department of Microbiology, College of Veterinary Medicine, The University of Tennessee, Knoxville 37996-0845, USA.
Deshpande
S P
SP
Rouse
B T
BT
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003319:Corneal Stroma / Q000276:immunology* / Q000473:pathology / Q000821:virology; D004797:Enzyme-Linked Immunosorbent Assay; D018259:Herpesvirus 1, Human / Q000276:immunology; D007124:Immunoenzyme Techniques; D007074:Immunoglobulin G / Q000032:analysis; D007371:Interferon-gamma / Q000378:metabolism; D016849:Keratitis, Herpetic / Q000276:immunology* / Q000473:pathology / Q000821:virology; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D018716:Molecular Mimicry; D010047:Ovalbumin / Q000276:immunology; D012313:RNA / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction
D007074:Immunoglobulin G; D012313:RNA; D007371:Interferon-gamma; D010047:Ovalbumin