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Jenna L. Burton, Cheng-Rong Yu, Yong-Jun Lee, Hyun-Mee Oh; IRF-8 Restrains T Cell Growth and Provides Protection From Activation Induced Cell Death. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2949.
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Interferon regulatory factors (IRFs) are a family of transcription factors involved in the regulation of cell growth, apoptosis, and immunological responses. Nine IRFs have been described and they are expressed in a variety of cells. However, IRF-8 (ICSBP) is thought to be expressed exclusively in myeloid and lymphoid cells, although, its expression has also been detected in the ocular lens. Even though its role in macrophages and dendritic cells is well established, it is intriguing that naïve T cells do not express IRF-8. However, T cells express IRF-8 in response to antigenic stimulation, suggesting that IRF-8 may be required for activation of genes that mediate T cell effector functions. In this study, we used mice with conditional deletion of IRF-8 in CD4+ T cells (CD4-IRF8KO) to study the function of IRF-8 in activated T cell subsets.
We generated mice with conditional deletion of IRF-8 in T cells (CD4-IRF8KO) by breeding IRF8fl/fl mice (kind gift from Herbert Morse, NIH) with mice that express Cre protein under direction of the CD4 promoter. Deletion of IRF-8 was confirmed by western blot analysis of protein extracts derived from TCR-activated CD4-IRF8KO T cells, and the homozygous CD4-IRF8KO mouse strain was established by several cycles of brother-sister mating. Wild type and CD4-IRF8KO T cells were stimulated with anti CD3/CD28 Abs and effects of IRF-8 on T cell proliferation, cell death, and T cell effector functions were examined by Thymidine incorporation assay, RT-PCR, western blot analysis, Annexin-V and intracellular cytokine staining assays.
We show that CD4-IRF8KO T cells exhibited significantly higher proliferative capacity as indicated by Thymidine incorporation assay and the expression of higher levels of cell surface markers, such as CD44. We also show that CD4-IRF8KO T cells were more susceptible to activation induced cell death and this correlated with enhanced expression of pro-apoptotic proteins, such as Bax and ICE.
Results obtained from studying CD4-IRF8KO mice reveal a previously unrecognized role of IRF-8 in T cells. The data suggests that IRF-8 may play a role in restraining T cell growth and conferring protection from activation induced cell death. Further studies using CD4-IRF8KO mice will undoubtedly reveal other functions of IRF-8 in activated T cells.
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