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J. Chen, C. Tan, B. P. Vistica, I. Gery, B. Detrick, J. J. Hooks; Interferon Beta Down-Regulates Cxcr3 on T Lymphocytes and Prevents Mice From Developing Immune-Mediated Ocular Inflammation. Invest. Ophthalmol. Vis. Sci. 2010;51(13):818. doi: https://doi.org/.
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IFN-beta can possess immunosuppressive activity and has been used in the treatment of diseases with a cerebral inflammation component such as multiple sclerosis. Although little has been done to investigate the mechanism, it has been suggested by our group that a critical role for RPE cell-derived IFN-beta in the down-regulation of CXCL9 protects retina from excessive inflammation (J Immunol 2008,180:3789). In this study we elucidated the immunoregulatory effects of IFN-beta on T cell CXCR3 expression in vitro and in a mouse model of Th1-mediated ocular inflammation, in which CXCR3 and its chemokines are critical for disease development.
Th cells expressing a hen egg lysozyme (HEL)-specific TCR were polarized in vitro by activation with HEL in the presence of type-specific cytokines and antibodies. Ocular inflammation was induced in HEL transgenic mice expressing HEL in the lens by adoptive transfer of Th1 cells. IFN-beta was administrated daily intraperitoneally into recipient mice. Protein and gene expression of CXCR3 was determined on T cells. Disease levels were assessed histologically.
IFN-beta down-regulated CXCR3 on CD4+ and CD8+ T cells (particularly on Th1 cells), in association with an increased CXCL10 signaling. Importantly, IFN-beta down-regulated CXCR3 on migratory Th1 cells in the spleen of recipient mice, that blocked T cells trafficking into the target eyes and prevented mice from developing Th1-mediated ocular inflammation. The decline in CXCR3 expression by migratory Th1 cells was determined by FACS analyses, associated with an IFN-beta induced CXCR3 chemokine signaling cascade in the spleen.
Our data demonstrate that the immunosuppression of IFN-beta seen in the mouse model of immune-mediated ocular inflammation is associated with re-navigation of T cell trafficking via IFN-beta mediated down-regulation of CXCR3. These observations therefore reveal a novel role of IFN-beta in the transduction of CXCR3 signaling for T cell migration.
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