The peptide sequence of diacyl lipopeptides determines dendritic cell TLR2-mediated NK activation

Masahiro Azuma, Ryoko Sawahata, Yuusuke Akao, Takashi Ebihara, Sayuri Yamazaki, Misako Matsumoto, Masahito Hashimoto, Koichi Fukase, Yukari Fujimoto, Tsukasa Seya

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38 Citations (Scopus)

Abstract

Natural killer (NK) cells are lymphocyte effectors that are activated to control certain microbial infections and tumors. Many NK-activating and regulating receptors are involved in regulating NK cell function. In addition, activation of näi{dotless}ve NK cells is fundamentally triggered by cytokines or myeloid dendritic cells (mDC) in various modes. In this study, we synthesized 16 S-[2,3-bis(palmitoyl)propyl]cysteine (Pam2Cys) lipopeptides with sequences designed from lipoproteins of Staphylococcus aureus, and assessed their functional properties using mouse (C57BL/6) bone marrow-derived DC (BMDC) and NK cells. NK cell activation was evaluated by three criteria: IFN-c production, up-regulation of NK activation markers and cytokines, and NK target (B16D8 cell) cytotoxicity. The diacylated lipopeptides acted as TLR2 ligands, inducing up-regulation of CD25/ CD69/CD86, IL-6, and IL-12p40, which represent maturation of BMDC. Strikingly, the Pam2Cys lipopeptides induced mouse NK cell activation based on these criteria. Cell-cell contact by Pam2Cys peptide-stimulated BMDC and NK cells rather than soluble mediators released by stimulated BMDC induced activation of NK cells. For most lipopeptides, the BMDC TLR2/ MyD88 pathway was responsible for driving NK activation, while some slightly induced direct activation of NK cells via the TLR2/MyD88 pathway in NK cells. The potential for NK activation was critically regulated by the peptide primary sequence. Hydrophobic or proline-containing sequences proximal to the N-terminal lipid moiety interfered with the ability of lipopeptides to induce BMDC-mediated NK activation. This mode of NK activation is distinctly different from that induced by polyI:C, which is closely associated with type I IFN-inducing pathways of BMDC. These results imply that the MyD88 pathway of BMDC governs an alternative NK-activating pathway in which the peptide sequence of TLR2-agonistic lipopeptides critically affects the potential for NK activation.

Original languageEnglish
Article numbere12550
Pages (from-to)1-12
Number of pages12
JournalPloS one
Volume5
Issue number9
DOIs
Publication statusPublished - 2010
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Azuma, M., Sawahata, R., Akao, Y., Ebihara, T., Yamazaki, S., Matsumoto, M., Hashimoto, M., Fukase, K., Fujimoto, Y., & Seya, T. (2010). The peptide sequence of diacyl lipopeptides determines dendritic cell TLR2-mediated NK activation. PloS one, 5(9), 1-12. [e12550]. https://doi.org/10.1371/journal.pone.0012550