Identification of Viral Antigens Recognized by Ocular Infiltrating T Cells from Patients with Varicella Zoster Virus-Induced Uveitis

• Published in: Investigative ophthalmology & visual science Vol. 48; no. 8; pp. 3689 - 3697
• Main Authors: Milikan, Johannes C. M, Kinchington, Paul R, Baarsma, G. Seerp, Kuijpers, Robert W. A. M, Osterhaus, Albert D. M. E, Verjans, Georges M. G. M
• Format: Journal Article
• Language: English
• Published: Rockville, MD ARVO 01.08.2007; Association for Research in Vision and Ophtalmology
• Subjects: Adolescent; Adult; Aged; Amino Acid Sequence; Antigens, Viral - genetics; Antigens, Viral - immunology; Aqueous Humor - cytology; Aqueous Humor - immunology; Aqueous Humor - virology; B-Lymphocytes - cytology; B-Lymphocytes - immunology; B-Lymphocytes - virology; Biological and medical sciences; Cell Line, Transformed; Cytokines - metabolism; Cytokines - secretion; Epitopes; Epitopes, T-Lymphocyte - immunology; Eye and associated structures. Visual pathways and centers. Vision; Female; Fundamental and applied biological sciences. Psychology; Herpes Zoster - complications; Herpes Zoster - immunology; Herpesvirus 3, Human - genetics; Herpesvirus 3, Human - immunology; Histocompatibility Antigens Class II - immunology; Humans; Immunologic Memory - immunology; Male; Medical sciences; Middle Aged; Molecular Sequence Data; Open Reading Frames - genetics; Open Reading Frames - immunology; Ophthalmology; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - virology; Th1 Cells - cytology; Th1 Cells - immunology; Th1 Cells - metabolism; Th1 Cells - virology; Uvea diseases; Uveitis - immunology; Uveitis - virology; Vertebrates: nervous system and sense organs; Human; Varicella zoster virus; Ocular; Herpesviridae; Alphaherpesvirinae; Uvea disease; Identification; Infection; Virus; Antigen; Eye disease; Viral disease; T-Lymphocyte; Uveitis; Ophthalmology
• DOI: 10.1167/iovs.07-0020
• ISSN: 0146-0404; 1552-5783

Varicella zoster virus (VZV) is a common cause of infectious uveitis associated with an intraocular inflammatory response involving virus-specific T cells. In the current study, the functional characteristics and the antigen specificity of VZV-reactive T cells recovered from intraocular fluid (IOF) samples of five patients with VZV were determined. B-cell lines were infected with a comprehensive panel of recombinant vaccinia viruses expressing 11 individual VZV open reading frames (ORFs), or alternatively pulsed with the corresponding peptides to generate antigen-presenting cells (APCs). T-cell responsiveness of the IOF-derived VZV-specific T cells toward APCs was monitored by interferon (IFN)-gamma enzyme-linked immunosorbent spot-forming assays on bulk T-cell cultures and subsequently T-cell clones (TCCs). The cytokine-secretion profile and cytotoxicity of the VZV-specific TCCs was determined by ELISA and flow cytometry, respectively. T-cell reactivity to VZV proteins encoded by ORF4, -10, -14, -18, -29, -31, -61, -62, -63, -67, and -68 was demonstrated, but specificity varied individually. T-cell epitopes on ORF62 and -68 were delineated. The TCCs secreted IFNgamma, but relatively low levels of interleukin-4 and -5, in response to VZV antigen-expressing APCs. The TCCs induced antigen-specific cytotoxic T-cell activity. The results suggest that the intraocular VZV-specific T-cell response in the patients with VZV analyzed is directed to a broad spectrum of VZV antigens, including the latency-associated VZV proteins from ORFs 4, 29, 63, and particularly ORF62. This local T-cell response was in part mediated by cytotoxic CD4(+) T cells with a Th1/0-like effector memory phenotype.