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.
Highlights
Receptor CD123 and are highly responsive to IL-3 stimulation[12]
In patients of Pitt-Hopkins Syndrome (PHS)[14], which is associated with E2-2 haploinsufficiency, all major immune cell types are present in normal numbers in peripheral blood except for pDCs
We selected four short hairpin RNAs for E2-2, all of which could knock down E2-2 expression in transfected 293T cells (Figure S1)
Summary
Mouse pDCs express low levels of IL-3 receptor and do not respond to IL-313. E2-2 is preferentially expressed in human and mouse pDCs, and has been identified as a key transcription factor for pDC development and cell fate maintenance[14,15]. Constitutive or conditional deletion of E2-2 blocks the development of mouse pDCs but not other lineages of immune cells. In patients of Pitt-Hopkins Syndrome (PHS)[14], which is associated with E2-2 haploinsufficiency, all major immune cell types are present in normal numbers in peripheral blood except for pDCs. In view of above differences between human and mouse pDCs, how E2-2 contributes to the species-specific differences is unclear yet. Function of E2-2 in human pDCs is in line with previous observation in mouse pDCs. Besides, cDNA array data indicates that E2-2 modulates the expression of some human specific genes including Siglec-6
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