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

Research output: Contribution to journalArticle

36 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

Fingerprint

lipopeptides
Lipopeptides
natural killer cells
dendritic cells
Natural Killer Cells
Dendritic Cells
bone marrow
Chemical activation
peptides
Peptides
Bone Marrow
Bone
cytokines
Up-Regulation
Interleukin-12 Subunit p40
Cytokines
mice
Lymphocytes
cells
Myeloid Cells

ASJC Scopus subject areas

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

Cite this

Azuma, M., Sawahata, R., Akao, Y., Ebihara, T., Yamazaki, S., Matsumoto, M., ... 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

The peptide sequence of diacyl lipopeptides determines dendritic cell TLR2-mediated NK activation. / Azuma, Masahiro; Sawahata, Ryoko; Akao, Yuusuke; Ebihara, Takashi; Yamazaki, Sayuri; Matsumoto, Misako; Hashimoto, Masahito; Fukase, Koichi; Fujimoto, Yukari; Seya, Tsukasa.

In: PLoS One, Vol. 5, No. 9, e12550, 2010, p. 1-12.

Research output: Contribution to journalArticle

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, vol. 5, no. 9, e12550, pp. 1-12. https://doi.org/10.1371/journal.pone.0012550
Azuma, Masahiro ; Sawahata, Ryoko ; Akao, Yuusuke ; Ebihara, Takashi ; Yamazaki, Sayuri ; Matsumoto, Misako ; Hashimoto, Masahito ; Fukase, Koichi ; Fujimoto, Yukari ; Seya, Tsukasa. / The peptide sequence of diacyl lipopeptides determines dendritic cell TLR2-mediated NK activation. In: PLoS One. 2010 ; Vol. 5, No. 9. pp. 1-12.
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