Staphylococcal Enterotoxin A Shapes Monocyte Transcription and Macrophage Polarization: Implications for Immune Responses in Infection and Inflammation

Staphylococcal enterotoxins (SE) crosslink the MHC-II on antigen-presenting cells (APC) with the T-cell receptor, inducing a polyclonal T-cell response. Although APCs are the initial targets of SE and are critical in shaping subsequent T-cell activation, the effects of SE on APC function remain poorly understood. This study investigates the immunomodulatory effects of staphylococcal enterotoxin A (SEA) on monocytes and their differentiation into monocyte-derived dendritic cells (moDC) or macrophages (MDM). Transcriptomic analyses of human monocytes via RNA sequencing revealed SEA-induced enrichment of gene pathways associated with inflammation, infection and dermatitis, effects that were amplified in the presence of T-cells. Phenotypic and functional characterization showed that SEA-primed monocytes differentiated into MDM with an altered polarization, deviating from classical M1/M2 pathways. SEA-primed MDM exhibited downregulayion of key markers including HLA-DR, CD80, CD86 and PD-L1. Functional assays demonstrated that SEA-primed MDM pushed hyperinflammatory T-cell responses, with significantly enhanced proliferation and IFN-? secretion. In contrast, moDC retained robust antigen-presenting capabilities even upon SEA-priming. These findings provide mechanistic insights into SEA-mediated immune modulation, illustrating how SEA reprograms MDM functions and amplify proinflammatory T-cell responses. This advances our understanding of superantigen-driven immune interactions, offering a foundation for developing therapeutic strategies to mitigate superantigen-mediated immune conditions. Overall design: RNA-seq profiling of human monocytes either unstimulated or stimulated with SEA or S. aureus cell-free supernatants for 24h