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J. Biol. Chem., Vol. 279, Issue 46, 48004-48012, November 12, 2004

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Human but Not Murine Toll-like Receptor 2 Discriminates between Tri-palmitoylated and Tri-lauroylated Peptides^*

Alina Grabiec, Guangxun Meng, Sylvia Fichte, Wolfgang Bessler, Hermann Wagner, and Carsten J. Kirschning¶

From the Institute of Medical Microbiology, Immunology, and Hygiene, Technical University of Munich, D-81675 Munich, Germany and the Institute of Molecular Medicine and Cell Research, Albert-Ludwig University of Freiburg, D-79104 Freiburg, Germany

Toll-like receptors (TLRs) mediate activation of the immune system upon challenge with microbial agonists, components of disintegrating cells of the body, or metabolic intermediates of lipidic nature. Comparison of murine (m) and human (h) TLR2 primary sequences revealed 65% of identical residues within the extracellular domains in contrast to 84% in the intracellular domains. Comparative analysis of TLR2-driven cell activation by various TLR2 agonists showed that the tri-lauroylated lipopeptide analog (Lau₃CSK₄) is recognized efficiently through mTLR2 but not hTLR2. Genetically complemented human embryonic kidney 293 cells and murine TLR2^-/- embryonic fibroblasts, as well as human and murine macrophage cells, were used for this analysis. In contrast to cellular activation, which depended on blockable access of the TLR2-ligand to TLR2, cellular uptake of Lau₃CSK₄ and tri-palmitoylated peptide (P₃CSK₄) was independent of TLR2. A low-conserved region spanning from leucine-rich repeat (LRR) motif 7 to 10 was found to control TLR2 species-specific cell activation. Exchange of mLRR8 for hLRR8 in mTLR2 abrogated mTLR2-typical cell activation upon cellular challenge with Lau₃CSK₄ but not P₃CSK₄, implicating mLRR8 as a central element of Lau₃CSK₄ recognition. The point mutation L112P within LRR3 abrogated hTLR2-dependent recognition of lipopeptides but merely attenuated mTLR2 function, whereas deletion of the N-terminal third of each LRR-rich domain (LRRs 1 to 7) had the opposite effect on P₃CSK₄ recognition. Despite similar domain structure of both TLR2 molecules, species-specific properties thus exist. Our results imply distinct susceptibilities of humans and mice to challenge with specific TLR2 ligands.

Received for publication, May 12, 2004 , and in revised form, August 26, 2004.

^* Supported by German Research Community Grants KI 591/1-1, SFB576/A1, and KI 591/1-5 (to A. G., G. M., and S. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Institute of Medical Microbiology, Immunology, and Hygiene, Technical University of Munich, Trogerstr. 4a, D-81675 Munich, Germany. Tel.: 49-89-4140-4132; Fax: 49-89-4140-4139; E-mail: carsten.kirschning{at}lrz.tum.de.

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