Submitted July 10, 2007
Accepted November 5, 2007
A common pathway mediated through Toll-like receptors leads to T and natural killer cell immunosuppression
Ilan Vaknin, Liora Blinder, Lynn Wang, Roi Gazit, Elena Shapira, Olga Genina, Mark Pines, Eli Pikarsky, and Michal Baniyash*
The Lautenberg Center for General and Tumor Immunology, The Hebrew University Hadassah Medical School, Jerusalem, Israel
Institute of Animal Science, ARO, The Volcani Center, Rehovot, Israel
Department of Pathology, Hebrew University Hadassah Medical School, Jerusalem, Israel
* Corresponding author; email: baniyash{at}cc.huji.ac.il.
T and NK cell immunosuppression associated with 
-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 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 -chain down-regulation mediated by myeloid suppressor cells, as observed in the course of active pathologies. We identified a 35 amino acid region within the -chain as being responsible for its degradation under TLR-mediated chronic inflammation. Furthermore, we provide evidence that -chain levels could serve as a biomarker for chronic inflammation-dependent immunosuppression. Thus, while 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.
