title: Functional characterization of ocular-derived human alphaherpesvirus cross-reactive CD4 T cells.
abstract: 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.
authors.affiliation: Department of Viroscience, Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands.
authors.forename: Werner J D
authors.initials: WJ
authors.lastname: Ouwendijk
authors.forename: Annemieke
authors.initials: A
authors.lastname: Geluk
authors.forename: Saskia L
authors.initials: SL
authors.lastname: Smits
authors.forename: Sarah
authors.initials: S
authors.lastname: Getu
authors.forename: Albert D M E
authors.initials: AD
authors.lastname: Osterhaus
authors.forename: Georges M G M
authors.initials: GM
authors.lastname: Verjans
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D000956:Antigens, Viral / Q000737:chemistry / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000821:virology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology; D002460:Cell Line; D017124:Conserved Sequence; D003429:Cross Reactions / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology; D018259:Herpesvirus 1, Human / Q000276:immunology*; D018258:Herpesvirus 2, Human / Q000276:immunology; D014645:Herpesvirus 3, Human / Q000276:immunology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000737:chemistry / Q000276:immunology; D007156:Immunologic Memory; D008213:Lymphocyte Activation / Q000276:immunology; D008969:Molecular Sequence Data; D010455:Peptides / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000235:genetics; D016415:Sequence Alignment; D015534:Trans-Activators / Q000737:chemistry / Q000276:immunology; D014605:Uveitis / Q000235:genetics / Q000276:immunology* / Q000821:virology*; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000276:immunology; D014779:Virus Replication
chemical_list: D000956:Antigens, Viral; D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; C074221:IE62 protein, Human herpesvirus 3; D017874:Immediate-Early Proteins; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D015534:Trans-Activators; D014759:Viral Envelope Proteins