Functional characterization of ocular-derived human alphaherpesvirus cross-reactive CD4 T cells

Intraocular varicella-zoster virus (VZV) and HSV type 1 (HSV-1) infections cause sight-threatening uveitis. The disease is characterized by an intraocular inflammatory response involving herpesvirus-specific T cells. T cell reactivity to the noncausative human alphaherpesvirus (αHHV) is commonly detected in the affected eyes of herpetic uveitis patients, suggesting the role of cross-reactive T cells in the disease. This study aimed to identify and functionally characterize intraocular human alphaherpesvirus cross-reactive T cells. VZV protein immediate early 62 (IE62), which shares extensive homology with HSV ICP4, is a previously identified T cell target in VZV uveitis. Two VZV-specific CD4 T cell clones (TCC), recovered from the eye of a VZV uveitis patient, recognized the same IE62918-927 peptide using different TCR and HLA-DR alleles. The IE62918-927 peptide bound with high affinity to multiple HLA-DR alleles and was recognized by blood-derived T cells of 5 of 17 HSV-1/VZV-seropositive healthy adults but not in cord blood donors (n = 5). Despite complete conservation of the IE62 epitope in the orthologous protein ICP4 of HSV-1 and HSV-2, the TCC recognized VZV and HSV-1- but not HSV-2-infected B cells. This was not attributed to proximal epitope-flanking amino acid polymorphisms in HSV-2 ICP4. Notably, VZV/HSV-1 cross-reactive CD4 T cells controlled VZV but not HSV-1 infection of human primary retinal pigment epithelium (RPE) cells. In conclusion, we report on the first VZV/HSV-1 cross-reactive CD4 T cell epitope, which is HLA-DR promiscuous and immunoprevalent in coinfected individuals. Moreover, ocular-derived peptide-specific CD4 TCC controlled VZV but not HSV-1 infection of RPE cells, suggesting that HSV-1 actively inhibits CD4 T cell activation by infected human RPE cells.