Abstract
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.
Highlights
Dendritic cells (DCs) orchestrate a variety of immune responses and are important players in responses to microbial infection, tumor immunity and autoimmunity [1]
We used a gain of function mutant of E protein transcription factors, ET2, to evaluate the role of E proteins in development of DCs in lymphoid and non-lymphoid tissue
Using two Cre transgenes that begin to express at different stages in hematopoiesis, we assessed the timing of ET2 expression on DC differentiation in homeostasis
Summary
Dendritic cells (DCs) orchestrate a variety of immune responses and are important players in responses to microbial infection, tumor immunity and autoimmunity [1]. Subsets of DCs are categorized as class 1 and class 2 conventional dendritic cells (cDC1 and cDC2), as well as plasmacytoid dendritic cells (pDC), each with specialized functions [2, 3]. PDCs are stimulated by intracellular nucleic acids arising during viral infection and produce large amounts of type I interferon. Despite their diverse functions, all DCs originate in the bone marrow mostly through common dendritic cell progenitors (CDP) [4,5,6], some lymphoid progenitors are known to give rise to pDCs [7]. CDPs branch into precursors of cDC (precDC) and pDC (pre-pDC) in the bone marrow. PrecDCs have been further divided into pre-cDC1 and pre-cDC2, which circulate in the blood and differentiate into their respective cDC classes in the periphery [8, 9]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
