IRF8 Transcription Factor Controls Survival and Function of Terminally Differentiated Conventional and Plasmacytoid Dendritic Cells, Respectively

Abstract

Interferon regulatory factor-8 (IRF8) has been proposed to be essential for development of monocytes, plasmacytoid dendritic cells (pDCs) and type 1 conventional dendritic cells (cDC1s) and remains highly expressed in differentiated DCs. Transcription factors that are required to maintain the identity of terminally differentiated cells are designated "terminal selectors." Using BM chimeras, conditional Irf8(fl/fl) mice and various promotors to target Cre recombinase to different stages of monocyte and DC development, we have identified IRF8 as a terminal selector of the cDC1 lineage controlling survival. In monocytes, IRF8 was necessary during early but not late development. Complete or late deletion of IRF8 had no effect on pDC development or survival but altered their phenotype and gene-expression profile leading to increased T cell stimulatory function but decreased type 1 interferon production. Thus, IRF8 differentially controls the survival and function of terminally differentiated monocytes, cDC1s, and pDCs.

All-trans retinoic acid and arsenic trioxide fail to derepress the monocytic differentiation driver Irf8 in acute promyelocytic leukemia cells

“…These observations are interesting within the context of the following three previous findings from other investigators: (1) the LSCs of APL probably differentiationally correspond to normal GMPs, 24, 34 and therefore possess a bipotent differentiation potential towards granulocytic or monocytic direction; (2) monocytic differentiation can be induced in certain APL cases and also in human APL cell lines; 36, 37 and (3) Irf8 itself is a master gene that drives the monoytic differentiation of normal MPs and also promotes the maturation and survival of DCs. 28, 38, 39, 40 Taken together, these observations suggest that the repressed Irf8 expression stands as a potentially crucial mechanism for the maintenance of the immaturity and malignancy of APL LSCs by precluding a possible monocytic maturation leakage. This notion was supported by the Dox-induced expression and knockdown experiments of Irf8 in APL cells, which showed a function role of Irf8 to drive monocytic/dendritic differentiation at the expense of granulocytic differentiation, to be accompanied by a reduction in the leukemogenesis of APL cells.…”

“…28, 38, 39, 40 Therefore, we hypothesized that Irf8 repression served as a key PML/RAR α -driven oncogenic mechanism to restrict monocytic/dendritic differentiation leakage of the APL progenitors, which otherwise would erode their leukemogenic potential. Consistent with this notion, PML/RAR α overexpression inhibited Irf8 induction, which was accompanied by DC differentiation retardation from the normal Lin − immature hematopoietic cells (Supplementary Figures S4a and b).…”

Myocardial Infarction Primes Autoreactive T Cells through Activation of Dendritic Cells

“…IRF4 was most highly expressed by cardiac cDC2s, whereas cDC1s expressed high levels of IRF8. Next, we crossed mice expressing CRE recombinase under the control of the CD11c promoter ( Cd11cCre mice) (Caton et al., 2007) with Irf4 flox (Persson et al., 2013) or Irf8 flox mice (Sichien et al., 2016) to generate mice lacking IRF4 or IRF8 expression, respectively, in CD11c + cells. Whenever CRE was expressed in CD11c + cells, Irf4 or Irf8 was efficiently floxed out and their protein levels declined (data not shown).…”

Functions of Murine Dendritic Cells

“…One of the earliest identified was the Irf8 −/− strain, which lacks cDC1s (Schiavoni et al, 2002; Aliberti et al, 2003), but also has impairments in B cells (Wang et al, 2008), monocytes (Kurotaki et al, 2013), eosinophils (Milanovic et al, 2008), and basophils (Sasaki et al, 2015). Irf8 −/− mice were also thought to lack pDCs (Schiavoni et al, 2002), but more recently it was determined that pDCs do not require IRF8 for their development but instead that loss of this factor affects their expression of cell-surface markers and their ability to produce interferon (Sichien et al, 2016). Irf8 −/− mice therefore do not serve as a model of specific cDC1 depletion, but this can be overcome by crossing a floxed Irf8 allele to the Itgax-cre strain (Luda et al, 2016), which depletes cDC1s and CD64 + CD11b + macrophages in the intestinal lamina propria, or to the Zbtb46-cre strain (Esterhazy et al, 2016), which specifically depletes cDC1s.…”