The transcription factor EHF promotes the maturation and immunosuppression of conventional dendritic cells.

The transcriptional program that regulates immunosuppression in CCR7(+) conventional dendritic cells (cDCs) is currently unknown. Here, we identify ETS homologous factor (EHF) as a transcription factor that regulates cDC maturation and immunosuppression after TLR7/8/9 stimulation. Mice with conditional deletion of EHF in DCs exhibit increased resistance to autoimmune, infection or tumor challenge. EHF-deficient DCs promotes Th1- and Th17-biased CD4(+) helper T cell response in vivo and in vitro. EHF-deficient cDC1s and cDC2s exhibit decreased expression of CCR7, CD200 and PD-L1, increased expression of DC-lineage transcriptional factor IRF4, and decreased expression of inhibitory NFκB family member Rel. EHF overexpression in DCs results in the opposite phenotype. CUT&TAG analysis suggests that EHF directly regulate Ccr7, Cd200, Cd274, Irf4 and Rel expression. Additionally, single-cell RNA-sequencing demonstrates that Ehf expression is highly enriched in CCR7(hi) DCs in mice and humans. Our study thus reveals a conserved transcriptional program that regulates cDC maturation and immunosuppression.