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Antigen/MHC Class II/Ig Dimers for Study of Uveitogenic T Cells: IRBP p161–180 Presented by both IA and IE Molecules

¹From the Laboratory of Immunology and the ⁴Genetics Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland; and the ⁵Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.

PURPOSE. Detection and modulation of effector T cells specific to immunodominant epitopes is a central issue in autoimmune diseases. Experimental autoimmune uveitis is a model for human autoimmune uveitis, induced in B10.RIII mice with interphotoreceptor retinoid binding protein or with its immunodominant epitope encoded by residues 161–180.

METHODS. The authors generated a dimer composed of p161–180 fused in frame to IA^r and mouse IgG1, and studied its effects on a CD4⁺ uveitogenic T-cell line specific to p161–180 and on a T-cell clone derived from that line.

RESULTS. Immunofluorescent staining of the T-cell line with the peptide/IA^r/Ig dimer revealed that about 90% of the cells bound the reagent, and 10% did not. The T-cell clone failed to bind the reagent. Consistent with this, the line proliferated when stimulated with the reagent plus anti-CD28, and the clone did not. Conversely, after being incubated with the reagent without CD28 cross-linking, the line showed decreased proliferation on subsequent stimulatory exposure to p161–180, whereas the clone was unaffected. Antigen-specific proliferation of splenocytes from B10.RIII mice primed with p161–180 was inhibited by anti-IA as well as anti-IE antibodies; proliferation of the T-cell line was inhibited strongly by anti-IA and poorly by anti-IE, and the clone showed the opposite pattern. Finally, the line, but not the clone, proliferated to p161–180 presented on a B-cell lymphoma expressing IA^r as its only restriction element.

CONCLUSIONS. Uveitogenic T cells can be detected as well as functionally modulated with their cognate peptide–class II reagent, suggesting the potential of such reagents for diagnostic and therapeutic use in uveitic disease; p161–180 can be presented by IA^r as well as IE^r major histocompatibility complex (MHC) class II molecules. The possibility that the same immunodominant fragment might be presented by more than one class II molecule should be taken into account when diagnostic or clinical use of peptide-MHC reagents is considered.

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