The normal brakes on an immune response
- Effector cells have short lifespans and die by apoptosis after the antigen is cleared
- Cytokine production falls when the triggering antigen or danger signal is removed
- IL-10 and TGF-\(\beta\) suppress further activation and promote regulatory T cell function
- Checkpoint receptors such as PD-1 and CTLA-4 raise the threshold for activation
- Soluble decoy receptors and IL-1 receptor antagonist buffer free cytokine
In a cytokine storm these brakes are overwhelmed, not missing. Cytokine production outruns the buffering capacity of decoy receptors and antagonists. The loop keeps recruiting new effector cells, so removing individual cells does not reduce total output. High TNF-\(\alpha\) and IL-6 impair regulatory T cell function and reduce dependence on costimulation, so checkpoint receptors lose leverage. Pyroptosis keeps releasing DAMPs, so the danger signal never clears and the stimulus persists.
The distinction matters for intervention: if the brakes were absent, replacing them would be the obvious strategy. Because they are present but outrun, the more effective approach is usually to reduce the amplification loop itself.