CD47-amyloid-β-CD74 signaling triggers adaptive immunosuppression in sepsis.

Summary

Using scRNA-seq and transcriptomics across blood, spleen, lymph nodes, and bone marrow, the authors show pervasive suppression of adaptive immunity in sepsis. They uncover a CD47-driven amyloid-β signal that engages CD74 on B cells to suppress adaptive responses; pharmacologic blockade restores immune function, reduces organ injury, and improves survival in septic mice. Sepsis-related gene signatures also discriminated sepsis from common infections in clinical datasets.

Key Findings

• scRNA-seq and RNA-seq reveal acute, systemic suppression of adaptive immunity across blood, spleen, lymph nodes, and bone marrow in sepsis.
• CD47 induces amyloid-β production that engages CD74 on B cells, suppressing B cells and adaptive immunity.
• Blocking CD47–Aβ signaling restores phagocyte function, reduces organ injury, and improves survival in septic mice.
• Adaptive immunity-related gene signatures distinguish sepsis from common infections in clinical datasets.

Clinical Implications

Suggests evaluating CD47 blockade, Aβ generation inhibitors, or CD74-targeted strategies to reverse sepsis-induced adaptive immunosuppression. Gene signatures may aid in distinguishing sepsis from common infections.

Limitations

• Translational uncertainty from mouse models to human therapeutic efficacy.
• Specificity and safety of targeting CD47–Aβ–CD74 in heterogeneous sepsis populations remain to be established.

Future Directions

Evaluate CD47/Aβ/CD74-targeted therapeutics in translational models and early-phase trials; validate gene signatures for clinical sepsis diagnostics.