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.