葡萄球菌肠毒素A调控单核细胞的转录及巨噬细胞的极化：其对感染和炎症过程中免疫反应的影响

《European Journal of Immunology》：Staphylococcal Enterotoxin A Shapes Monocyte Transcription and Macrophage Polarization: Implications for Immune Responses in Infection and Inflammation

SEA通过调节单核细胞分化为树突状细胞（moDC）和巨噬细胞（MDM）影响免疫反应，moDC增强T细胞增殖和IFN-γ分泌，MDM表面标志物（HLA-DR、CD80、CD86、PD-L1）显著下调，促进过度炎症。

　　
Staphylococcal enterotoxin A (SEA) is a well-characterized superantigen produced by *Staphylococcus aureus* that induces robust T-cell activation by cross-linking MHC-II molecules on antigen-presenting cells (APCs) with T-cell receptors (TCRs). While previous studies have focused on the adaptive immune response mediated by T cells, the impact of SEA on innate immune cells, particularly monocytes and their differentiated counterparts, remains underexplored. This study systematically investigates how SEA modulates the transcriptional profiles, phenotypes, and functional outcomes of monocytes as they differentiate into dendritic cells (DCs) and macrophages (MDMs), with a specific focus on their interactions with T cells.

### Key Findings on Monocyte Transcriptional Reprogramming
The study begins by analyzing the transcriptional changes in human monocytes exposed to SEA. RNA sequencing revealed significant upregulation of genes involved in inflammation (e.g., CXCL9, CXCL10, IL15RA), T-cell activation (CD80, CD86, PDL1), and immune regulation (SOCS1, GBP5). Conversely, genes associated with tissue repair (FN1) and immune tolerance (KLF2, HGF) were downregulated. Notably, these changes were more pronounced in the presence of T cells, suggesting a synergistic effect between SEA and T-cell signaling to amplify immune activation. Pathway analysis further highlighted the enrichment of infection, inflammation, and dermatitis-related pathways, aligning with SEA's role in driving proinflammatory responses and its association with skin diseases like atopic dermatitis.

### Impact on Dendritic Cell Differentiation
When isolated monocytes were primed with SEA and differentiated into moDCs, the study observed minimal changes in surface markers (CD11c, DC-SIGN, CCR7) or activation status (CD83). However, SEA-primed moDCs exhibited enhanced T-cell interaction markers (CD40, ICAM1) and increased production of T-cell-attracting chemokines (CXCL9, CCL17). When co-cultured with autologous T cells, SEA-primed moDCs significantly promoted T-cell proliferation and IFN-γ secretion, even in the absence of external stimulation. This suggests that SEA primes monocytes to generate moDCs that act as potent activators of adaptive immunity, potentially contributing to chronic inflammatory conditions.

### Distinct Effects on Macrophage Polarization
In contrast to moDCs, SEA-primed monocytes influenced MDM differentiation. For M1-like MDMs (activated by IFN-γ and LPS), SEA reduced surface expression of HLA-DR, CD80, and CD86, while lowering the frequency of cells expressing these markers. This downregulation was particularly evident in the M2-like MDMs (activated by IL-4), where SEA also suppressed PD-L1 and CD163, molecules associated with immune tolerance and macrophage regulation. Despite these phenotypic shifts, the cytokine profiles (TNF, IL-6, IL-10) remained largely unchanged, indicating that SEA primarily altered MDM activation status rather than their capacity to secrete inflammatory mediators.

### T-Cell Response Modulation
The study reveals that SEA-primed MDMs, even without T-cell co-stimulation, enhanced T-cell proliferation and proinflammatory cytokine production (IFN-γ, TNF). This effect was more pronounced than in cells primed with β-glucan (a tolerogenic stimulus) or LPS (a classical activator). However, the absence of IL-2 secretion in the long-term co-culture suggests that SEA's priming effect might rely on transient T-cell activation rather than sustained cytokine feedback. The differential impact of SEA on moDCs versus MDMs underscores the complexity of APC function and highlights the need for context-specific studies.

### Mechanistic Insights and Clinical Implications
The findings suggest that SEA acts as a dual modulator: it enhances innate immune activation by reprogramming monocyte transcription and promoting APC maturation, while simultaneously dampening regulatory pathways (e.g., SOCS1, RGS2). This creates a paradoxical situation where SEA primes APCs to both amplify inflammation and suppress anti-inflammatory signals. In the context of skin diseases, this mechanism could explain why SEA exposure correlates with atopic dermatitis and asthma— SEA-primed MDMs in the skin microenvironment might perpetuate chronic inflammation by promoting T-cell activation while inhibiting immune tolerance.

### Limitations and Future Directions
The study acknowledges limitations, including the use of isolated monocytes rather than whole PBMCs, which may overlook APC interactions with other innate cells (e.g., neutrophils). Additionally, the lack of clinical samples limits the direct translation to human diseases. Future research could explore how SEA primes APCs in different tissues (e.g., lung, gut) and how this impacts diseases like toxic shock syndrome (TSS) or food allergies. therapeutic strategies targeting SEA-induced APC reprogramming could be critical, particularly in conditions where hyperinflationary T-cell responses drive pathology.

### Conclusion
This research advances the understanding of SEA's immunomodulatory effects beyond T-cell activation. By reprogramming monocytes into APCs with altered effector functions, SEA creates a self-reinforcing cycle of inflammation. The differential responses of moDCs (enhanced antigen presentation) and MDMs (diminished regulatory markers) suggest that therapeutic interventions may need to target specific APC subsets. For example, blocking SEA-induced CD80/CD86 upregulation in moDCs might reduce T-cell hyperactivation, while restoring PD-L1 expression in MDMs could mitigate chronic inflammation. These insights position SEA as a key player in the pathogenesis of superantigen-mediated diseases and highlight APC reprogramming as a potential therapeutic axis.