TY - JOUR
T1 - Metabolic sialic acid blockade lowers the activation threshold of moDCs for TLR stimulation
AU - Büll, Christian
AU - Collado-Camps, Estel
AU - Kers-Rebel, Esther D
AU - Heise, Torben
AU - Søndergaard, Jonas N
AU - den Brok, Martijn H
AU - Schulte, Barbara M
AU - Boltje, Thomas J
AU - Adema, Gosse J
PY - 2017/4/1
Y1 - 2017/4/1
N2 - 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.
AB - 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.
KW - Antigens, CD/metabolism
KW - Antigens, Differentiation/metabolism
KW - Antigens, Differentiation, Myelomonocytic/metabolism
KW - Biomimetics
KW - Cell Differentiation
KW - Cells, Cultured
KW - Cytokines/metabolism
KW - Dendritic Cells/drug effects
KW - Humans
KW - Lectins/metabolism
KW - Lipopolysaccharides/immunology
KW - Lymphocyte Activation/drug effects
KW - Lymphocyte Culture Test, Mixed
KW - Monocytes/immunology
KW - N-Acetylneuraminic Acid/analogs & derivatives
KW - Poly I-C/immunology
KW - Sialic Acid Binding Immunoglobulin-like Lectins/metabolism
KW - Sialic Acids/pharmacology
KW - Signal Transduction/drug effects
KW - T-Lymphocytes/immunology
KW - Toll-Like Receptors/metabolism
U2 - 10.1038/icb.2016.105
DO - 10.1038/icb.2016.105
M3 - Journal article
C2 - 27874015
SN - 0818-9641
VL - 95
SP - 408
EP - 415
JO - Immunology and Cell Biology
JF - Immunology and Cell Biology
IS - 4
ER -
