Lymphatic specific disruption in the fine structure of heparan sulfate inhibits dendritic cell traffic and functional T cell responses in the lymph node.
Dendritic cells (DCs) are potent APCs essential for initiating adaptive immunity. Following pathogen exposure, trafficking of DCs to lymph nodes (LNs) through afferent lymphatic vessels constitutes a crucial step in the execution of their functions. The mechanisms regulating this process are poorly understood, although the involvement of certain chemokines in this process has recently been reported. In this study, we demonstrate that genetically altering the fine structure (N-sulfation) of heparan sulfate (HS) specifically in mouse lymphatic endothelium significantly reduces DC trafficking to regional LNs in vivo. Moreover, this alteration had the unique functional consequence of reducing CD8(+) T cell proliferative responses in draining LNs in an ovalbumin immunization model. Mechanistic studies suggested that lymphatic endothelial HS regulates multiple steps during DC trafficking, including optimal presentation of chemokines on the surface of DCs, thus acting as a co-receptor that may function "in trans" to mediate chemokine receptor binding. This study not only identifies novel glycan-mediated mechanisms that regulate lymphatic DC trafficking, but it also validates the fine structure of lymphatic vascular-specific HS as a novel molecular target for strategies aiming to modulate DC behavior and/or alter pathologic T cell responses in lymph nodes.
Marine Drug Research Institute, Huaihai Institute of Technology, Lianyungang 222005, China;
Xin
X
Yin
Scott C
SC
Johns
Daniel
D
Kim
Zbigniew
Z
Mikulski
Catherina L
CL
Salanga
Tracy M
TM
Handel
Mónica
M
Macal
Elina I
EI
Zúñiga
Mark M
MM
Fuster
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D018925:Chemokines / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D004729:Endothelium, Lymphatic / Q000166:cytology / Q000276:immunology*; D006497:Heparan Sulfate / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic
D018925:Chemokines; D006497:Heparan Sulfate