Dual Function of the IRF8 Transcription Factor in Autoimmune Uveitis: Loss of IRF8 in T Cells Exacerbates Uveitis, Whereas Irf8 Deletion in the Retina Confers Protection

Abstract

Interferon regulatory factor 8 (IRF8) is constitutively expressed in monocytes and B cells and plays critical role in the functional maturation of microglia cells. It is induced in T-cells following antigen stimulation but its functions are less well understood. However, recent studies in mice with T cell-specific Irf8 disruption under direction of the Lck promoter (LCK-IRF8KO) suggest that IRF8 directs a silencing program for Th17 differentiation and IL-17 production is markedly increased in IRF8 deficient T-cells. Paradoxically, loss of IRF8 in T-cells has no effect on the development or severity of experimental autoimmune encephalomyelitis (EAE) while exacerbating colitis in a mouse colitis model. On the other hand, mice with a macrophage/microglia-specific Irf8 disruption are resistant to EAE, further confounding our understanding of the roles of IRF8 in host immunity and autoimmunity. To clarify the role of IRF8 in autoimmune diseases, we have generated two mouse strains with targeted deletion of Irf8 in retinal cells including microglial cells and a third mouse strain with targeted Irf8 deletion in T-cells under direction of the non-promiscuous, CD4 promoter (CD4-IRF8KO). In contrast to the report that IRF8 deletion in T-cells has no effect on EAE, experimental autoimmune uveitis is exacerbated in CD4-IRF8KO mice and disease enhancement correlates with significant expansion of Th17 cells and a reduction in Tregs. In contrast to CD4-IRF8KO mice, Irf8 deletion in retinal cells confers protection from uveitis, underscoring divergent and tissue-specific roles of IRF8 in host immunity. These results raise cautionary note in context of therapeutic targeting of IRF8.

An osteopontin/CD44 immune checkpoint controls CD8+ T cell activation and tumor immune evasion

“…IRF8 regulates myeloid cell differentiation through repressing granulocyte development and promoting differentiation of monocytic cells such as dendritic cells and macrophages (39)(40)(41)(42)(43). IRF8 functions in hematopoietic cell differentiation and activation have since been extended to other hematopoietic cells, including B, NK, and T cells (25,31,41,(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56). However, IRF8 functions in T cells are apparently tissue-and disease-specific (25,30,38,46,53,57).…”

Enhancer Connectome Nominates Target Genes of Inherited Risk Variants from Inflammatory Skin Disorders

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The expression profiles and regulation of PD-L1 in tumor-induced myeloid-derived suppressor cells

“…IRF proteins function as master transcription factors to regulate gene expression in various cell types, particularly in myeloid cells. 1,9,49,50 Analysis of the nine known IRF family members indicated that treatment of J774M cells with IFNg upregulated expression of IRF1, IRF5, IRF7 and IRF8 (Figs. S1C and D).…”