Metabolic sialic acid blockade lowers the activation threshold of moDCs for TLR stimulation

Immunol Cell Biol. 2017 Apr;95(4):408-415. doi: 10.1038/icb.2016.105. Epub 2016 Nov 22.

Abstract

Sialic acid sugars cover the surface of dendritic cells (DCs) and have been suggested to impact several aspects of DC biology. Research into the role of sialic acids in DCs, however, is complicated by the limited number of tools available to modulate sialic acid expression. Here we report on a synthetic, fluorinated sialic acid mimetic, Ac53FaxNeu5Ac, which potently blocks sialic acid expression in human monocyte-derived DCs (moDCs). Sialic acid blockade enhanced the responsiveness of moDCs to Toll-like receptor (TLR) stimulation as measured by increased maturation marker expression and cytokine production. Consequently, the T-cell activation capacity of Ac53FaxNeu5Ac-treated moDCs was strongly increased. In addition to sialic acids, moDCs also expressed the sialic acid-binding immunoglobulin-like lectins (Siglecs) -3, -5, -7, -9 and -10, immune inhibitory receptors recognizing these sialic acids. Treatment with Ac53FaxNeu5Ac abrogated putative cis and trans interactions between sialic acids and Siglec-7/-9. Together, these data indicate that sialic acids limit the activation of moDCs via the TLR pathway, potentially by interacting with Siglec-7 or Siglec-9. Metabolic sialic acid blockade with Ac53FaxNeu5Ac could therefore potentially be used to generate more potent DC-based vaccines for induction of robust anti-viral or anti-tumor immune responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / metabolism
  • Antigens, Differentiation / metabolism
  • Antigens, Differentiation, Myelomonocytic / metabolism
  • Biomimetics
  • Cell Differentiation
  • Cells, Cultured
  • Cytokines / metabolism
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology*
  • Humans
  • Lectins / metabolism
  • Lipopolysaccharides / immunology
  • Lymphocyte Activation / drug effects*
  • Lymphocyte Culture Test, Mixed
  • Monocytes / immunology
  • N-Acetylneuraminic Acid / analogs & derivatives
  • N-Acetylneuraminic Acid / antagonists & inhibitors
  • N-Acetylneuraminic Acid / pharmacology*
  • Poly I-C / immunology
  • Sialic Acid Binding Immunoglobulin-like Lectins / metabolism
  • Sialic Acids / pharmacology*
  • Signal Transduction / drug effects*
  • T-Lymphocytes / immunology*
  • Toll-Like Receptors / metabolism

Substances

  • Ac53FaxNeu5Ac
  • Antigens, CD
  • Antigens, Differentiation
  • Antigens, Differentiation, Myelomonocytic
  • Cytokines
  • Lectins
  • Lipopolysaccharides
  • SIGLEC7 protein, human
  • SIGLEC9 protein, human
  • Sialic Acid Binding Immunoglobulin-like Lectins
  • Sialic Acids
  • Toll-Like Receptors
  • N-Acetylneuraminic Acid
  • Poly I-C