Glycosylation-dependent interactions of C-type lectin DC-SIGN with colorectal tumor-associated Lewis glycans impair the function and differentiation of monocyte-derived dendritic cells
Glycosylation-dependent interactions of C-type lectin DC-SIGN with colorectal tumor-associated Lewis glycans impair the function and differentiation of monocyte-derived dendritic cells
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DOI：
10.4049/jimmunol.180.5.3347
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发表时间：
2008-03-01
影响因子：
4.4
通讯作者：
Kawasaki, Toshisuke
中科院分区：
文献类型：
--
作者：
Nonaka, Motohiro;Ma, Bruce Yong;Kawasaki, Toshisuke
树突状细胞（Dendritic cells，DCs）是一种重要的APC，在先天免疫和适应性免疫中起着重要的桥梁作用。DC特异性细胞间粘附分子3-抓取非整合素（DC-SIGN）是DC上表达的主要C型凝集素之一，对非唾液酸化刘易斯（Le）聚糖具有高亲和力。最近，我们报道了SW 1116上表达的寡糖配体的表征，SW 1116是一种典型的人结直肠癌，被甘露聚糖结合蛋白识别，甘露聚糖结合蛋白是一种血清C型凝集素，具有与DC-SIGN相似的碳水化合物识别特异性。这些肿瘤特异性寡糖配体显示包含Le（a）/Le（B）表位的串联重复簇。在这项研究中，我们发现DC-SIGN通过识别癌胚抗原（CEA）和CEA相关细胞粘附分子1（CEACAM 1）上的Le（a）/Le（B）聚糖的异常糖基化形式参与了DC与SW 1116细胞的相互作用。含有Le（a）/Le（B）聚糖的DC-SIGN配体也在原发性结肠癌上皮细胞上高度表达，但在正常结肠上皮细胞上不表达，并且DC-SIGN被认为通过DC-SIGN识别这些癌症相关的Le聚糖配体而参与DC和结肠直肠癌细胞之间的原位缔合。此外，当单核细胞衍生的DC（MoDC）与SW 1116细胞共培养时，LPS诱导的免疫抑制细胞因子如IL-6和IL-10增加。阻断抗DC-SIGN抗体可显著抑制上述作用。值得注意的是，LPS诱导的MoDC成熟被与SW 1116细胞共培养的上清液抑制。我们的研究结果表明，结直肠癌通过DC-SIGN和结直肠肿瘤相关的Le聚糖之间的相互作用影响DC功能和分化，可能会诱导宿主产生有效的抗肿瘤反应。
Dendritic cells (DCs) are APCs that play an essential role by bridging innate and adaptive immunity. DC-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) is one of the major C-type lectins expressed on DCs and exhibits high affinity for nonsialylated Lewis (Le) glycans. Recently, we reported the characterization of oligosaccharide ligands expressed on SW1116, a typical human colorectal carcinoma recognized by mannan-binding protein, which is a serum C-type lectin and has similar carbohydrate-recognition specificities as DC-SIGN. These tumor-specific oligosaccharide ligands were shown to comprise clusters of tandem repeats of Le(a)/Le(b) epitopes. In this study, we show that DC-SIGN is involved in the interaction of DCs with SW1116 cells through the recognition of aberrantly glycosylated forms of Le(a)/Le(b) glycans on carcinoembryonic Ag (CEA) and CEA-related cell adhesion molecule 1 (CEACAM1). DC-SIGN ligands containing Le(a)/Le(b) glycans are also highly expressed on primary cancer colon epithelia but not on normal colon epithelia, and DC-SIGN is suggested to be involved in the association between DCs and colorectal cancer cells in situ by DC-SIGN recognizing these cancer-related Le glycan ligands. Furthermore, when monocyte-derived DCs (MoDCs) were cocultured with SW1116 cells, LPS-induced immunosuppressive cytokines such as IL-6 and IL-10 were increased. The effects were significantly suppressed by blocking Abs against DC-SIGN. Strikingly, LPS-induced MoDC maturation was inhibited by supernatants of cocultures with SW1116 cells. Our findings imply that colorectal carcinomas affecting DC function and differentiation through interactions between DC-SIGN and colorectal tumor-associated Le glycans may induce generalized failure of a host to mount an effective antitumor response.