Th17 cells, which secrete interleukin 17 (IL-17) and IL-22 comprise a recently identified subset of CD4+ T cells distinct from the Th1 and Th2 subsets. More and more evidence indicates that Th17 cells are involved in the pathogenesis of various autoimmune/inflammatory diseases. Thus, a more complete understanding of the molecular mechanisms involved in the regulation of Th17 immune responses would provide insights into the pathogenesis and treatment of chronic inflammatory diseases. Although RORgt is necessary and sufficient for the generation of Th17 cells, the molecular mechanisms underlying the phenotypic and functional diversity of Th17 cells are not fully understood. We now find that interferon regulatory factor (IRF) 8, a transcription factor of the IRF family, plays a critical role in the control of Th17 cell differentiation. IRF8-deficiency in both conventional and T cell specific conditional knock out mice leads to more robust Th17 cell differentiation without effects on either Th1 or Th2 cell lineages. Furthermore, transfer of IRF8-/- CD4+CD45Rbhi cells into RAG-/- mice induces more severe colitis compared to control CD4+CD45Rbhi cells. In addition, mice reconstituted with IRF8-/- cells had a significantly higher percentage of IL-17-producing cells than control mice. The results suggest that IRF8 negatively regulates the development of Th17 immune response resulting in the control of inflammation. Furthermore, we have demonstrated that IRF8 physically interacts with RORgt resulting in the suppression of IL-17 transcription. These findings define a novel transcriptional inhibitor of Th17 cell differentiation and highlight the importance of intrinsic genetic programs directing the silence for Th17 immune response. Since Th17 immune response is important for human inflammatory diseases, it is critical to define the function of IRF8 in Th17, Th1, and Th2 cell differentiation, to elucidate in detail how IRF8 is regulated in T cells, and to characterize expression of IRF8 in the different cell compartments (macrophages, dendritic cells and T cells) in the development of colitis.

Public Health Relevance

Crohn's disease is a chronic inflammatory disease of the digestive or gastrointestinal (GI) tract and Th17 immune response has recently been suggested to be involved in the development of disease. We demonstrate that transcription factor IRF8 inhibits the Th17 immune response in mice and in the proposal we will further explore the function of IRF8 on human Th17 cell differentiation and characterize expression of IRF8 in different cell compartments in the control of Th17 cell differentiation. This research will shed light on IRF8 as a potential therapeutic target for therapy in Crohn’s disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56AI091871-01A1
Application #
8305224
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Rothermel, Annette L
Project Start
2011-09-01
Project End
2012-12-31
Budget Start
2011-09-01
Budget End
2012-12-31
Support Year
1
Fiscal Year
2011
Total Cost
$423,750
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Wang, Juan; Peng, Liang; Zhang, Ruihua et al. (2016) 5-Fluorouracil targets thymidylate synthase in the selective suppression of TH17 cell differentiation. Oncotarget 7:19312-26
Geng, Shuo; Chen, Keqiang; Yuan, Ruoxi et al. (2016) The persistence of low-grade inflammatory monocytes contributes to aggravated atherosclerosis. Nat Commun 7:13436
Lu, Geming; Zhang, Ruihua; Geng, Shuo et al. (2015) Myeloid cell-derived inducible nitric oxide synthase suppresses M1 macrophage polarization. Nat Commun 6:6676
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
Jianjun Yang; Zhang, Ruihua; Lu, Geming et al. (2013) T cell–derived inducible nitric oxide synthase switches off Th17 cell differentiation. J Exp Med 210:1447-62
Zhang, Ruihua; Li, Qin; Chuang, Peter Y et al. (2013) Regulation of pathogenic Th17 cell differentiation by IL-10 in the development of glomerulonephritis. Am J Pathol 183:402-12
Zhang, Ruihua; Chen, Kang; Peng, Liang et al. (2012) Regulation of T helper cell differentiation by interferon regulatory factor family members. Immunol Res 54:169-76
Greter, Melanie; Helft, Julie; Chow, Andrew et al. (2012) GM-CSF controls nonlymphoid tissue dendritic cell homeostasis but is dispensable for the differentiation of inflammatory dendritic cells. Immunity 36:1031-46