Cellular recognition of microbial patterns through toll-like receptor (TLR) 2

Toll-like receptor (TLR) 2 mediates cellular recognition of microbial products. It has not been elucidated previously whether TLR2 binds its agonists directly or whether binding of an endogenous spaetzle-like ligand initiates receptor signaling as is exemplified by cell activation through the prototype TLR "toll" of Drosophila. We found by mutational analysis of the TLR2-ectodomain (ED) that distinct agonists utilize different subdomains of the TLR2-ED. Correspondingly, the TLR2-ED N-terminal third is excluded from TLR2-dependent cell activation by tri- and di-acylated bacterial lipopeptides but is involved in recognition of other TLR2 agonists. MAb T2.5 was found to antagonize both murine and human TLR2 and inhibited inflammatory reactions in systemic models of infection. Our data implicate binding of microbial products to specific epitopes of the TLR2-ED and mAb-mediated TLR-blockage for prevention of septic shock.