Immune responses to retinal self-antigens in CD25(+)CD4(+) regulatory T-cell-depleted mice.
OBJECTIVE
Prior work has shown that autoimmune uveoretinitis develops spontaneously in CD25(+)CD4(+) regulatory T-cell-depleted mice (Tr-depleted mice). In this study, the generation of autoantibodies and autoreactive T-cells specific to retinal antigens was examined in Tr-depleted mice with uveoretinitis, and the pathogenic and immunogenic abilities of the autoreactive T cells were evaluated.


METHODS
Tr-depletion was achieved in (C57BL/6 x A/J) F1 (B6A) mice by thymectomy on day 3 of life followed by intraperitoneal injection of an anti-CD25 mAb. At 6 months of age, autoantibodies to the retina were evaluated by indirect immunofluorescence, and total IgG2a levels in sera were assessed by ELISA. The pathogenic abilities of the splenic T cells were examined by adoptive transfer to syngeneic nu/nu mice, and the proliferation responses and the secretion of granulocyte-macrophage-colony-stimulating factor (GM-CSF), IFN-gamma, and IL-10 on stimulation by retinal self-antigens was also evaluated.


RESULTS
Autoantibodies to the retinal photoreceptor cell layer were detected in Tr-depleted mice, and the titers correlated well with the grades of inflammatory lesions. The splenic CD4(+) T cells of Tr-depleted mice induced uveoretinitis in the recipients by adoptive transfer and exhibited proliferative responses and secretion of IFN-gamma, but not of IL-10, by in vitro stimulation with S-Ag and interphotoreceptor retinoid-binding protein (IRBP). Moreover, the total IgG2a level in serum was markedly and significantly augmented in Tr-depleted mice.


CONCLUSIONS
The results suggest that in Tr-depleted mice in which uveoretinitis develops, S-Ag and IRBP-specific T cells are spontaneously sensitized and shifted to a Th1-phenotype. These sensitized T cells may account for the development of autoimmune uveoretinitis in Tr-depleted mice.
Takeuchi
Masaru
M
Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan. takeuchi@tokyo-med.ac.jp
Keino
Hiroshi
H
Kezuka
Takeshi
T
Usui
Masahiko
M
Taguchi
Osamu
O
D019264:Adoptive Transfer; D000818:Animals; D019393:Arrestin / Q000276:immunology; D001323:Autoantibodies / Q000097:blood*; D001324:Autoantigens / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002417:Cattle; D004268:DNA-Binding Proteins / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D019084:Fluorescent Antibody Technique, Indirect; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D007074:Immunoglobulin G / Q000097:blood; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000276:immunology; D020419:Photoreceptor Cells, Vertebrate / Q000276:immunology*; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D012173:Retinitis / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D014605:Uveitis / Q000276:immunology
D019393:Arrestin; D001323:Autoantibodies; D001324:Autoantigens; D004268:DNA-Binding Proteins; D007074:Immunoglobulin G; D009687:Nuclear Proteins; D015375:Receptors, Interleukin-2; D016753:Interleukin-10; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor