EFB Dengue Literature Review

IRF4

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IRF4

Overview

IRF4 (Interferon Regulatory Factor 4) is a transcription factor essential for plasma cell differentiation. IRF4 and IRF8 reciprocally regulate each other to determine plasma cell vs. germinal centre fates: high IRF4 with low IRF8 drives PC differentiation, while the reverse promotes GC B cell identity. In DN2 cells, the IRF4/IRF8 ratio is shifted toward PC fate.

Key Points from Literature

  • High IRF4, low IRF8 in DN2 cells: IRF4 transcription is higher in SLE DN2 cells than SWM; IRF8 is lower in DN2 than any other B cell subset. The IRF4/IRF8 ratio is significantly lower (i.e., skewed toward IRF4) in aNAV and DN2 cells relative to other subsets in both HCD and SLE — consistent with promotion of a PC rather than memory fate (see Jenks2018 - DN2 B Cells and EF Pathway in SLE, RNA-seq + flow cytometry n=5 HCD + n=5 SLE).

  • IRF4 target gene enrichment: GSEA shows that DN2 cells transcribe higher amounts of IRF4 target genes expressed by PC, relative to SWM. Genes with binding motifs for IRF4 and its co-factor SPI1 (PU.1) are enriched in the DN2 transcriptome (see Jenks2018 - DN2 B Cells and EF Pathway in SLE).

  • Low ETS1 amplifies IRF4 effect: DN2 cells express low ETS1, a TF that represses PC differentiation. ETS1 deficiency leads to accumulation of extrafollicular autoreactive B cells (citing Russell et al. 2015). The combination of high IRF4 and low ETS1 in the absence of BACH2 creates a transcriptional environment strongly biased toward PC differentiation (see Jenks2018 - DN2 B Cells and EF Pathway in SLE).

  • IRF4 listed as entity in COVID-19 EF ASC context: Woodruff2020 identifies IRF4 among the transcription factors relevant to the EF-derived ASC programme in severe COVID-19, consistent with the IRF4-high/IRF8-low signature defined in SLE DN2 cells (see Woodruff2020 - EF B Cell Responses in COVID-19, n=17 COVID-19 prospective cohort).

  • IRF4 motifs enriched in ABC chromatin: In SWEF-deficient lupus mice, ABC chromatin shows enhanced accessibility in areas enriched for T-bet, AP-1, and IRF4 binding motifs — the same motifs enriched in human SLE DN2 cells. IRF4 is thus part of a conserved mouse-human ABC regulatory programme (see Sanz2025 - Human Atypical B Cells Overview, review).

Contradictions & Debates

None documented in current wiki sources.

BLIMP-1, DN2 B Cell, Plasmablast, BACH2, Extrafollicular Response

Sources

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