The Peptide Sequence of Diacyl Lipopeptides Determines Dendritic Cell TLR2-Mediated NK Activation

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概要

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• 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 naïve 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-γ 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 polyl: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.

• 2010-09-02

著者

• Ebihara Takashi

  北海道大学 医学研究科免疫学

• Matsumoto Misako

  北海道大学 医学研究科免疫学

• Matsumoto M

  Department Of Microbiology And Immunology Hokkaido University Graduate School Of Medicine

• Seya Tsukasa

  大阪府立成人病センター研究所 免疫学部門

• Seya Tsukasa

  北海道大学 医学研究科免疫学

• Seya Tsukasa

  Department Of Immunology Osaka Medical Center For Cancer And Cardiovascular Diseases:probrain

• Fukase K

  Osaka Univ. Coll. Sci. Osaka

• Fukase K

  Osaka Univ. Osaka

• Fukase Koichi

  Dep. Of Chemistry Graduate School Of Sci. Osaka Univ.

• Fujimoto Yukari

  Department Of Chemistry Graduate School Of Science Osaka University

• Ebihara Takashi

  Department Of Microbiology And Immunology Hokkaido University Graduate School Of Medicine

• 松本 美佐子

  Department Of Microbiology And Immunology Hokkaido University Graduate School Of Medicine

• Hashimoto M

  Department Of Macromolecular Science And Engineering Graduate School Of Science And Technology Kyoto

• Hashimoto M

  Department Of Polymer Science And Engineering Faculty Of Textile Science Kyoto Institute Of Technolo

• Seto Toshiyuki

  Daparment Of Virology

• Matsumoto Masanori

  Laboratory Of Immunodynamics Department Of Microbiology And Immunology Osaka University Graduate Sch

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