A common pathway mediated through Toll-like receptors leads to T- and natural killer-cell immunosuppression.
T- and natural killer (NK)-cell immunosuppression associated with zeta-chain down-regulation 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 zeta-chain down-regulation mediated by myeloid suppressor cells, as observed in the course of active pathologies. We identified a 35-amino acid (aa) region within the zeta-chain as being responsible for its degradation under TLR-mediated chronic inflammation. Furthermore, we provide evidence that zeta-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.
Vaknin
Ilan
I
Lautenberg Center for General and Tumor Immunology, Hebrew University Hadassah Medical School, Jerusalem, Israel.
Blinder
Liora
L
Wang
Lynn
L
Gazit
Roi
R
Shapira
Elena
E
Genina
Olga
O
Pines
Mark
M
Pikarsky
Eli
E
Baniyash
Michal
M
D000818:Animals; D015415:Biomarkers; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D007108:Immune Tolerance / Q000276:immunology*; D007249:Inflammation / Q000276:immunology; D029521:Alphainfluenzavirus / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D015398:Signal Transduction / Q000276:immunology*; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology*
D015415:Biomarkers; D008024:Ligands; D008070:Lipopolysaccharides; D051193:Toll-Like Receptors