{"doi":"10.1016/j.jbc.2023.105579","title":"The glycoimmune checkpoint receptor Siglec-7 interacts with T-cell ligands and regulates T-cell activation","abstract":"Siglec-7 (sialic acid-binding immunoglobulin-like lectin 7) is a glycan-binding immune receptor that is emerging as a significant target of interest for cancer immunotherapy. The physiological ligands that bind Siglec-7, however, remain incompletely defined. In this study, we characterized the expression of Siglec-7 ligands on peripheral immune cell subsets and assessed whether Siglec-7 functionally regulates interactions between immune cells. We found that disialyl core 1 O-glycans are the major immune ligands for Siglec-7 and that these ligands are particularly highly expressed on naïve T-cells. Densely glycosylated sialomucins are the primary carriers of these glycans, in particular a glycoform of the cell-surface marker CD43. Biosynthesis of Siglec-7-binding glycans is dynamically controlled on different immune cell subsets through a genetic circuit involving the glycosyltransferase GCNT1. Siglec-7 blockade was found to increase activation of both primary T-cells and antigen-presenting dendritic cells in vitro, indicating that Siglec-7 binds T-cell glycans to regulate intraimmune signaling. Finally, we present evidence that Siglec-7 directly activates signaling pathways in T-cells, suggesting a new biological function for this receptor. These studies conclusively demonstrate the existence of a novel Siglec-7-mediated signaling axis that physiologically regulates T-cell activity. Going forward, our findings have significant implications for the design and implementation of therapies targeting immunoregulatory Siglec receptors.","journal":"Journal of Biological Chemistry","year":2023,"id":323194,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":38,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9571,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":415376,"name":"J.M. Daly","orcid":"0000-0001-5497-0473","position":1,"is_corresponding":false},{"id":1038555,"name":"Olivia Drummond-Guy","orcid":null,"position":2,"is_corresponding":false},{"id":1037898,"name":"Vignesh Krishnamoorthy","orcid":"0000-0003-3408-4815","position":3,"is_corresponding":false},{"id":562118,"name":"Jessica C. Stark","orcid":"0000-0003-3828-5438","position":4,"is_corresponding":false},{"id":218283,"name":"Nicholas M. Riley","orcid":"0000-0002-1536-2966","position":5,"is_corresponding":false},{"id":1037899,"name":"Karla C. Williams","orcid":"0000-0003-2954-2869","position":6,"is_corresponding":false},{"id":218284,"name":"Carolyn R. Bertozzi","orcid":"0000-0003-4482-2754","position":7,"is_corresponding":false},{"id":218281,"name":"Simon Wisnovsky","orcid":"0000-0003-4010-4309","position":8,"is_corresponding":false},{"id":949887,"name":"Natalie Stewart","orcid":"0000-0002-9192-2515","position":0,"is_corresponding":true}],"reference_count":68,"raw_metadata":null,"created_at":"2026-07-19T01:07:52.377944Z","pmid":"38141764","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}