Collins Brian E, Blixt Ola, Han Shoufa, Duong Bao, Li Hongyi, Nathan Jay K, Bovin Nicolai, Paulson James C
Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92024, USA.
J Immunol. 2006 Sep 1;177(5):2994-3003. doi: 10.4049/jimmunol.177.5.2994.
CD22 (Siglec-2) is a key regulator of B cell signaling whose function is modulated by interaction with extracellular glycan ligands mediated through its N-terminal Ig domain. Its preferred ligand is the sequence Sia alpha2-6Gal that is abundantly expressed on N-linked glycans of B cell glycoproteins, and by binding to CD22 in cis causes CD22 to appear "masked" from binding to synthetic sialoside probes. Yet, despite the presence of cis ligands, CD22 redistributes to sites of cell contact by binding to trans ligands on neighboring cells. In this study, we demonstrate the dynamic equilibrium that exists between CD22 and its cis and trans ligands, using a high-affinity multivalent sialoside probe that competes with cis ligands and binds to CD22 on native human and murine B cells. Consistent with the constitutive endocytosis reported for CD22, the probes are internalized once bound, demonstrating that CD22 is an endocytic receptor that can carry ligand-decorated "cargo" to intracellular compartments. Conjugation of the sialoside probes to the toxin saporin resulted in toxin uptake and toxin-mediated killing of B lymphoma cell lines, suggesting an alternative approach for targeting CD22 for treatment of B cell lymphomas.
CD22（唾液酸结合免疫球蛋白样凝集素-2）是B细胞信号传导的关键调节因子，其功能通过与细胞外聚糖配体相互作用来调节，这种相互作用由其N端免疫球蛋白结构域介导。其首选配体是序列Siaα2-6Gal，该序列在B细胞糖蛋白的N-连接聚糖上大量表达，通过顺式结合CD22使CD22看起来“被掩盖”而无法与合成唾液酸苷探针结合。然而，尽管存在顺式配体，CD22仍通过与相邻细胞上的反式配体结合而重新分布到细胞接触部位。在本研究中，我们使用一种高亲和力多价唾液酸苷探针，该探针与顺式配体竞争并结合天然人和鼠B细胞上的CD22，证明了CD22与其顺式和反式配体之间存在动态平衡。与报道的CD22组成型内吞作用一致，探针一旦结合就会被内化，这表明CD22是一种内吞受体，可以将携带配体的“货物”运送到细胞内区室。唾液酸苷探针与毒素皂草素的偶联导致毒素摄取和毒素介导的B淋巴瘤细胞系杀伤，提示了一种靶向CD22治疗B细胞淋巴瘤的替代方法。
