Innate immune responses are dictated by a panel of pathogen recognition receptors, downstream signaling from the receptors and the stimulated activities of various effector molecules. IRF8 is known as an interferon (IFN)-responsive transcription factor that plays critical roles in regulating the development of myeloid and dendritic cells and the activity of a number of genes, such as IL-12 and iNOS, involved in innate responses. Much of the activity of IRF8 in vitro was previously shown to require its ability to heterodimerize with PU.1 and possibly other transcription factors to mediate transcriptional activation or repression. An in vivo test of this model was provided by studies of BXH2 mice that identified a point mutation in IRF8 in the domain required for heterodimerization. It was shown that mice bearing this mutation were very similar to those bearing a null mutation of the gene, but that the null and point-mutant mice differed in their patterns of dendritic cell maturation. This indicated that most, but not all in vivo activities of IRF8 are dependent on its ability to dimerize with other transcription factors. Previous studies demonstrated that IRF8 is expressed to varying extents in subsets of dendritic cells (DC) of bone marrow origin. The status of IRF8 expression in follicular dendritic cells (FDC) that are not of bone marrow origin was not known. Studies of human and mouse FDC demonstrated that they expressed little or no IRF8. In addition, it was found also that IRF8 is expressed a much lower levels in tingible body macrophages of germinal centers than in other macrophage subsets. Studies of IRF8 knockout mice showed that the distribution and number of marginal zone macrophages was greatly altered while metallophilic macrophages on the other side of the marginal sinus were unaffected. These findings indicated that IRF8 was differentially expressed and functional in subsets of DC and macrophages. The function of IRF8 was previously shown by us and our collaborators to be affected by partnering with TRIM21, a member of the tripartite family and genes and and E3 ubiquitin ligase. To examine the role(s) played by TRIM21 in biology we generated a TRIM21 knockout mouse with an EGFP reporter inserted into the gene. Remarkably, the mouse exhibited essentially not abnormalities in innate immunity mediated by hematopoietic cells but was shown to negatively regulate NF-KB dependent proinflammatory responses in fibroblasts. We published a review on the contributions of the entire TRIM family to innate and acquired immunity including responses to HIV.

Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2010
Total Cost
$575,177
Indirect Cost
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Sakai, Tomomi; Miyazaki, Takuya; Shin, Dong-Mi et al. (2017) DNase-active TREX1 frame-shift mutants induce serologic autoimmunity in mice. J Autoimmun 81:13-23
Yan, Ming; Wang, Hongsheng; Sun, Jiafang et al. (2016) Cutting Edge: Expression of IRF8 in Gastric Epithelial Cells Confers Protective Innate Immunity against Helicobacter pylori Infection. J Immunol 196:1999-2003
Sun, Lin; St Leger, Anthony J; Yu, Cheng-Rong et al. (2016) Interferon Regulator Factor 8 (IRF8) Limits Ocular Pathology during HSV-1 Infection by Restraining the Activation and Expansion of CD8+ T Cells. PLoS One 11:e0155420
Paschall, Amy V; Zhang, Ruihua; Qi, Chen-Feng et al. (2015) IFN regulatory factor 8 represses GM-CSF expression in T cells to affect myeloid cell lineage differentiation. J Immunol 194:2369-79
Sasaki, Haruka; Kurotaki, Daisuke; Osato, Naoki et al. (2015) Transcription factor IRF8 plays a critical role in the development of murine basophils and mast cells. Blood 125:358-69
Xu, Yulian; Jiang, Lei; Fang, Jianchen et al. (2015) Loss of IRF8 Inhibits the Growth of Diffuse Large B-cell Lymphoma. J Cancer 6:953-61
Gupta, Monica; Shin, Dong-Mi; Ramakrishna, Lakshmi et al. (2015) IRF8 directs stress-induced autophagy in macrophages and promotes clearance of Listeria monocytogenes. Nat Commun 6:6379
Kim, Sung-Hye; Burton, Jenna; Yu, Cheng-Rong et al. (2015) 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. J Immunol 195:1480-8
Yoon, Jeongheon; Feng, Xianxum; Kim, Yong-Soo et al. (2014) Interferon regulatory factor 8 (IRF8) interacts with the B cell lymphoma 6 (BCL6) corepressor BCOR. J Biol Chem 289:34250-7
Carotta, Sebastian; Willis, Simon N; Hasbold, Jhagvaral et al. (2014) The transcription factors IRF8 and PU.1 negatively regulate plasma cell differentiation. J Exp Med 211:2169-81

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