The ETS-family transcription factor PU.1 is a critical regulator of the inhibitory Fcγ receptor IIB expression in humans.

The inhibitory Fc gamma receptor IIB (FcγRIIB) is a critical determinant of humoral immunity. By providing feedback inhibition, through inhibitory signalling or competition for antibody Fc engagement, it counterbalances and contextualises cellular responses to signals emanating from co-ligated activating receptors, such as the B-cell receptor and activating FcγR. These activities collectively suppress the emergence of B- cell-mediated autoimmune disease and immune complex-mediated pathologies. However, FcγRIIB upregulation within the tumour microenvironment limits the efficacy of monoclonal antibody (mAb)-mediated immunotherapy of cancer. While the functional significance of FcγRIIB is well established in mice, its physiological roles and the regulatory mechanisms governing its expression remain incompletely understood in humans. Here we characterise the molecular determinants of FcγRIIB expression in human immune models and primary cells. Our findings reveal that the ETS-family transcription factor PU.1 plays a crucial role in regulating basal and inducible FcγRIIB expression. Moreover, when co-expressed, PU.1 co-operates with the related ETS-family member SPIB to drive FcγRIIB expression. PU.1 binding to the proximal FcγRIIB promoter elicits transcription, at least in part, through recruitment of the CBP/p300 transcriptional co-activators. Interestingly, similar mechanisms are also observed at the proximal promoters of the activating FcγRI and FcγRIIA, suggesting that additional, potentially lineage specific, factors cooperate with PU.1 to drive the distinct expression patterns of these FcγR. These insights pave the way for future investigations aimed at understanding the molecular mechanisms responsible for cell lineage-specific FcγR expression and subsequently manipulating them for therapeutic purposes.