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Lin Sun, Anthony St Leger, Chengrong Yu, Chang He, Rashid M Mahdi, Chi-Chao Chan, CHRALES E EGWUAGU; Interferon regulator factor 8 (IRF-8) limits ocular pathology during HSV-1 infection by restricting the activation and expansion of CD8 T cell . Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4842.
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Interferon Regulatory Factor 8 (IRF-8) plays an important role in myeloid and B cell differentiation. Although expression of IRF-8 is induced in T cells in response to antigen stimulation, its role in T cell mediated regulation of immune responses or host immunity is still unknown. In this study, we have used an ocular herpes simplex virus 1 (HSV-1) infection model to investigate the function of IRF-8 in CD8 T cell mediated control of viral infection.
We generated mice with targeted deletion of IRF-8 in the CD4 compartment (CD4-IRF-8KO) by breeding IRF-8fl/fl mouse (kindly provided by Dr. Herbert Morse, NIH) with mice expressing Cre recombinase under the CD4 promoter (CD4/Cre mice). WT and CD4-IRF8KO mice were infected with HSV-1 by corneal scarification and HSV-specific CD8 T cell responses were examined and characterized using the virus-specific gB-Tetramer reagent, flow cytometry and intracellular cytokine staining assays. Viral clearance was determined by plaque assay and ocular pathology was assessed by histological analysis.
Compared to WT, the CD4-IRF8KO mice generated robust immune responses characterized by increased numbers of virus-specific CD8 T cells and markedly elevated levels of pro-inflammatory cytokines, resulting in excessive ocular inflammation. CD4-IRF8KO CD8 T cells expressed high levels of chemokine receptors and up-regulation of the chemotactic molecules facilitated the infiltration of protective CD8 T cells into the trigeminal ganglia (TG). In addition, viral clearance in the eyes of CD4-IRF8KO mice was found to correlate with a dramatic increase of HSV-specific CD8 T cells in the TG.
The data presented here suggest that an important function of IRF-8 in T cells may be to restrain lymphocyte activation, proliferation and to regulate the expression of molecules that mediate lymphocyte chemotaxis. Specifically, loss of IRF-8 led to exuberant inflammatory response, resulting in exacerbated immune-mediated ocular pathology in HSV-1 infected mice. Our data showing that IRF-8 suppresses T cell expansion and effector functions suggest that IRF-8 is a potential therapeutic target that can be exploited to mitigate pathological autoimmunity.
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