1. Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA
2. EU Joint Research Centre, ECVAM, I-21020 Ispra, Italy
3. Research Center Borstel, Leibniz-Center for Medicine and Biosciences, 23845 Borstel, Germany

Correspondence to: Bruce Beutler¹ Correspondence and requests for materials should be addressed to B.B. (Email: bruce@scripps.edu).

Abstract

Toll-like receptor 2 (TLR2) is required for the recognition of numerous molecular components of bacteria^{1, 2, 3, 4, 5, 6, 7, 8}, fungi^{9, 10} and protozoa¹¹. The breadth of the ligand repertoire seems unusual, even if one considers that TLR2 may form heteromers with TLRs 1 and 6 (ref. 12), and it is likely that additional proteins serve as adapters for TLR2 activation. Here we show that an N-ethyl-N-nitrosourea-induced nonsense mutation of Cd36 (oblivious) causes a recessive immunodeficiency phenotype in which macrophages are insensitive to the R-enantiomer of MALP-2 (a diacylated bacterial lipopeptide) and to lipoteichoic acid. Homozygous mice are hypersusceptible to Staphylococcus aureus infection. Cd36^obl macrophages readily detect S-MALP-2, PAM₂CSK₄, PAM₃CSK₄ and zymosan, revealing that some—but not all—TLR2 ligands are dependent on CD36. Already known as a receptor for endogenous molecules, CD36 is also a selective and nonredundant sensor of microbial diacylglycerides that signal via the TLR2/6 heterodimer.

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