Augmenting E Protein Activity Impairs cDC2 Differentiation at the Pre-cDC Stage
Dendritic cell (DC) specification and differentiation are controlled by a circuit of transcription factors, which regulate the expression of DC effector genes as well as the transcription factors themselves. E proteins are a widely expressed basic helix-loop-helix family of transcription factors who...
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doaj-5d15fae4bf904c0a9da21411efd3de972020-12-18T06:21:13ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-12-011110.3389/fimmu.2020.577718577718Augmenting E Protein Activity Impairs cDC2 Differentiation at the Pre-cDC StageSandra Bajana0Kevin Thomas1Constantin Georgescu2Ying Zhao3Jonathan D. Wren4Susan Kovats5Xiao-Hong Sun6Program in Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, United StatesProgram in Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, United StatesProgram in Genes and Human Diseases, Oklahoma Medical Research Foundation, Oklahoma City, OK, United StatesProgram in Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, United StatesProgram in Genes and Human Diseases, Oklahoma Medical Research Foundation, Oklahoma City, OK, United StatesProgram in Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, United StatesProgram in Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, United StatesDendritic cell (DC) specification and differentiation are controlled by a circuit of transcription factors, which regulate the expression of DC effector genes as well as the transcription factors themselves. E proteins are a widely expressed basic helix-loop-helix family of transcription factors whose activity is suppressed by their inhibitors, ID proteins. Loss-of-function studies have demonstrated the essential role of both E and ID proteins in different aspects of DC development. In this study, we employed a gain-of-function approach to illustrate the importance of the temporal control of E protein function in maintaining balanced differentiation of conventional DC (cDC) subsets, cDC1 and cDC2. We expressed an E protein mutant, ET2, which dimerizes with endogenous E proteins to overcome inhibition by ID proteins and activate the transcription of E protein targets. Induction of ET2 expression at the hematopoietic progenitor stage led to a dramatic reduction in cDC2 precursors (pre-cDC2s) with little impact on pre-cDC1s. Consequently, we observed decreased numbers of cDC2s in the spleen and lung, as well as in FLT3L-driven bone marrow-derived DC cultures. Furthermore, in mice bearing ET2, we detected increased expression of the IRF8 transcription factor in cDC2s, in which IRF8 is normally down-regulated and IRF4 up-regulated. This aberrant expression of IRF8 induced by ET2 may contribute to the impairment of cDC2 differentiation. In addition, analyses of the transcriptomes of splenic cDC1s and cDC2s revealed that ET2 expression led to a shift, at least in part, of the transcriptional profile characteristic of cDC2s to that of cDC1. Together, these results suggest that a precise control of E protein activity is crucial for balanced DC differentiation.https://www.frontiersin.org/articles/10.3389/fimmu.2020.577718/fullE proteincDC1cDC2pre-cDCIRF4IRF8 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sandra Bajana Kevin Thomas Constantin Georgescu Ying Zhao Jonathan D. Wren Susan Kovats Xiao-Hong Sun |
spellingShingle |
Sandra Bajana Kevin Thomas Constantin Georgescu Ying Zhao Jonathan D. Wren Susan Kovats Xiao-Hong Sun Augmenting E Protein Activity Impairs cDC2 Differentiation at the Pre-cDC Stage Frontiers in Immunology E protein cDC1 cDC2 pre-cDC IRF4 IRF8 |
author_facet |
Sandra Bajana Kevin Thomas Constantin Georgescu Ying Zhao Jonathan D. Wren Susan Kovats Xiao-Hong Sun |
author_sort |
Sandra Bajana |
title |
Augmenting E Protein Activity Impairs cDC2 Differentiation at the Pre-cDC Stage |
title_short |
Augmenting E Protein Activity Impairs cDC2 Differentiation at the Pre-cDC Stage |
title_full |
Augmenting E Protein Activity Impairs cDC2 Differentiation at the Pre-cDC Stage |
title_fullStr |
Augmenting E Protein Activity Impairs cDC2 Differentiation at the Pre-cDC Stage |
title_full_unstemmed |
Augmenting E Protein Activity Impairs cDC2 Differentiation at the Pre-cDC Stage |
title_sort |
augmenting e protein activity impairs cdc2 differentiation at the pre-cdc stage |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2020-12-01 |
description |
Dendritic cell (DC) specification and differentiation are controlled by a circuit of transcription factors, which regulate the expression of DC effector genes as well as the transcription factors themselves. E proteins are a widely expressed basic helix-loop-helix family of transcription factors whose activity is suppressed by their inhibitors, ID proteins. Loss-of-function studies have demonstrated the essential role of both E and ID proteins in different aspects of DC development. In this study, we employed a gain-of-function approach to illustrate the importance of the temporal control of E protein function in maintaining balanced differentiation of conventional DC (cDC) subsets, cDC1 and cDC2. We expressed an E protein mutant, ET2, which dimerizes with endogenous E proteins to overcome inhibition by ID proteins and activate the transcription of E protein targets. Induction of ET2 expression at the hematopoietic progenitor stage led to a dramatic reduction in cDC2 precursors (pre-cDC2s) with little impact on pre-cDC1s. Consequently, we observed decreased numbers of cDC2s in the spleen and lung, as well as in FLT3L-driven bone marrow-derived DC cultures. Furthermore, in mice bearing ET2, we detected increased expression of the IRF8 transcription factor in cDC2s, in which IRF8 is normally down-regulated and IRF4 up-regulated. This aberrant expression of IRF8 induced by ET2 may contribute to the impairment of cDC2 differentiation. In addition, analyses of the transcriptomes of splenic cDC1s and cDC2s revealed that ET2 expression led to a shift, at least in part, of the transcriptional profile characteristic of cDC2s to that of cDC1. Together, these results suggest that a precise control of E protein activity is crucial for balanced DC differentiation. |
topic |
E protein cDC1 cDC2 pre-cDC IRF4 IRF8 |
url |
https://www.frontiersin.org/articles/10.3389/fimmu.2020.577718/full |
work_keys_str_mv |
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