Characterization of species-specific genes regulated by E2-2 in human plasmacytoid dendritic cells

Abstract

Dendritic cells (DCs) are sentinels of the immune system and comprise two distinct subsets: conventional DCs (cDCs) and plasmacytoid DCs (pDCs). Human pDCs are distinguished from mouse pDCs phenotypically and functionally. Basic helix-loop-helix protein E2-2 is defined as an essential transcription factor for mouse pDC development, cell fate maintenance and gene programe. It is unknown whether E2-2 regulation contributes to this species-specific difference. Here we investigated the function of E2-2 in human pDCs and screened human-specific genes regulated by E2-2. Reduced E2-2 expression in human pDC cell line GEN2.2 resulted in diminished IFN-α production in response to CpG but elevated antigen presentation capacity. Gene expression profiling showed that E2-2 silence down-regulated pDC signature genes but up-regulated cDC signature genes. Thirty human-specific genes regulated by E2-2 knockdown were identified. Among these genes, we confirmed that expression of Siglec-6 was inhibited by E2-2. Further more, Siglec-6 was expressed at a higher level on a human pDC subset with drastically lower expression of E2-2. Collectively, these results highlight that E2-2 modulates pDC function in a species-specific manner, which may provide insights for pDC development and functions.

Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors

“…5A and fig. S6A) (18–19). In contrast, CD123 + CD11C −/lo AS DCs expressed cDC markers, including CD2 , CX3CR1 , CD33 /SIGLEC3, CD5 , and SIGLEC1 /CD169, both at protein and mRNA levels (Fig.…”

Regulation of Transcription Factor E2-2 in Human Plasmacytoid Dendritic Cells by Monocyte-Derived TNFα

“…In mice, inducible knockout of E2-2 gives rise to a cell that is markedly decreased in its ability to produce IFNs but more adapted to stimulate T cell responses [15]. This is recapitulated in human pDC cell lines where E2-2 knockdown decreases IFN production and increases the ability to induce T cell proliferation [15,17], though pDC leukemic cells lines produce little or no IFN and do not fully represent primary human pDC function [20][21][22][23]. It has also been demonstrated that mouse and human pDCs downregulate E2-2 in response to chronic viral infection [16,19].…”

“…STAT3, in turn promotes the expression of transcription factor E2-2 (TCF4) [11]. E2-2 is required for pDC development [10,11,15,16] and promotes canonical pDC phenotype and function [17].…”

“…E2-2 is highly expressed in pDCs and at low levels in mDCs and B cells. In pDCs, E2-2 promotes several archetypal pDC genes, such as SPIB, ILT7 and TLR7/9, and represses mDC-associated genes [4,10,17]. In mice, whole system E2-2 knockout ablates all pDC development [10,16], while inducible knockout of E2-2 in peripheral pDCs causes a conversion to an mDC-like cell with altered phenotype and function [15].…”

“…Studies of pDCs have indicated that mature pDCs alter E2-2 expression in response to a variety of stimuli [16,19]. In vitro, human pDC cell lines that downregulate E2-2 exhibit a similar phenotype and function as described in murine E2-2 knockout pDCs [17]. However, human pDC cell lines do not completely recapitulate the transcriptional and functional profile of primary pDCs [20].…”