Innate Immune Activation Is a Strong Suppressor of CCL22 and Impedes Regulatory T Cell-Dendritic Cell Interaction.

Summary

Innate immune activation via TLR, RLH, and STING signaling robustly suppresses CCL22 in lymphoid organs and dendritic cells, reducing regulatory T cell–dendritic cell clustering. In vivo Salmonella infection reproduced this suppression, and sepsis patients exhibited decreased serum CCL22, linking this mechanism to human disease.

Key Findings

• TLR, RLH, and STING activation strongly downregulated CCL22 expression and secretion by dendritic cells.
• Inflammatory cytokines (IFN-α, IFN-γ, IL-10) mediated CCL22 suppression following TLR activation by B and T cells.
• Reduced CCL22 correlated with fewer Treg–DC clusters in vitro; in vivo Salmonella typhimurium infection lowered CCL22 in lymphoid organs.
• Sepsis patients had significantly decreased serum CCL22 compared to controls.

Clinical Implications

CCL22 reduction in sepsis may serve as a biomarker of an early proinflammatory phase when Treg support is diminished, informing immunophenotyping and potential stage-specific immunotherapies.

Limitations

• Predominantly preclinical mouse and in vitro data; human sample size and clinical heterogeneity not detailed.
• Causality for outcomes in human sepsis not established; interventional validation lacking.

Future Directions

Test whether modulating the CCL22–Treg–DC axis improves pathogen clearance without exacerbating immunopathology in sepsis; evaluate CCL22 as a stratification biomarker in adaptive immunotherapy trials.