FUT6 deficiency compromises basophil function by selectively abrogating their sialyl-Lewis x expression

• Main Authors: Puan, Kia Joo, San Luis, Boris, Nurhashikin Yusof, Kumar, Dilip, Andiappan, Anand Kumar, Lee, Wendy, Cajic, Samanta, Vuckovic, Dragana, Chan, Jing De, Döllner, Tobias, Hou, Han Wei, Jiang, Yunxuan, Tian, Chao, Rapp, Erdmann, Poidinger, Michael, Wang, De Yun, Soranzo, Nicole, Lee, Bernett, Rötzschke, Olaf
• Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
• Format: Article
• Language: English
• Published: 2022
• Subjects: Science::Medicine; Engineering::Mechanical engineering; Mast-Cells; T-Cells
• Online Access: https://hdl.handle.net/10356/154951
• Institution: Nanyang Technological University

Sialyl-Lewis x (sLex, CD15s) is a tetra-saccharide on the surface of leukocytes required for E-selectin-mediated rolling, a prerequisite for leukocytes to migrate out of the blood vessels. Here we show using flow cytometry that sLex expression on basophils and mast cell progenitors depends on fucosyltransferase 6 (FUT6). Using genetic association data analysis and qPCR, the cell type-specific defect was associated with single nucleotide polymorphisms (SNPs) in the FUT6 gene region (tagged by rs17855739 and rs778798), affecting coding sequence and/or expression level of the mRNA. Heterozygous individuals with one functional FUT6 gene harbor a mixed population of sLex+ and sLex- basophils, a phenomenon caused by random monoallelic expression (RME). Microfluidic assay demonstrated FUT6-deficient basophils rolling on E-selectin is severely impaired. FUT6 null alleles carriers exhibit elevated blood basophil counts and a reduced itch sensitivity against insect bites. FUT6-deficiency thus dampens the basophil-mediated allergic response in the periphery, evident also in lower IgE titers and reduced eosinophil counts.