T- and natural killer (NK)-cell immunosuppression associated with ζ-chain downregulation has been described in cancer, autoimmune, and infectious diseases. However, the precise stimuli leading to this bystander phenomenon in such different pathogen-dependent and sterile pathologies remained unresolved. Here, we demonstrate that Toll-like receptors (TLRs) play a major role in the induction of innate and adaptive immune system suppression; repetitive administration of single TLR 2, 3, 4, or 9 agonists, which do not exhibit any virulent or immune invasive properties, was sufficient to induce a bystander NK- and T-cell immunosuppression associated with ζ-chain downregulation mediated by myeloid suppressor cells, as observed in the course of active pathologies. We identified a 35-amino acid (aa) region within the ζ-chain as being responsible for its degradation under TLR-mediated chronic inflammation. Furthermore, we provide evidence that ζ-chain levels could serve as a biomarker for chronic inflammation-dependent immunosuppression. Thus, although acute TLR-mediated activation could be beneficial in clearing pathogens or may serve as an immune adjuvant, such activation could be detrimental under sustained conditions.