{"doi":"10.1073/pnas.2302370120","title":"CD44 acts as a coreceptor for cell-specific enhancement of signaling and regulatory T cell induction by TGM1, a parasite TGF-β mimic","abstract":"Long-lived parasites evade host immunity through highly evolved molecular strategies. The murine intestinal helminth, Heligmosomoides polygyrus , down-modulates the host immune system through release of an immunosuppressive TGF-β mimic, TGM1, which is a divergent member of the CCP (Sushi) protein family. TGM1 comprises 5 domains, of which domains 1-3 (D1/2/3) bind mammalian TGF-β receptors, acting on T cells to induce Foxp3 + regulatory T cells; however, the roles of domains 4 and 5 (D4/5) remain unknown. We noted that truncated TGM1, lacking D4/5, showed reduced potency. Combination of D1/2/3 and D4/5 as separate proteins did not alter potency, suggesting that a physical linkage is required and that these domains do not deliver an independent signal. Coprecipitation from cells treated with biotinylated D4/5, followed by mass spectrometry, identified the cell surface protein CD44 as a coreceptor for TGM1. Both full-length and D4/5 bound strongly to a range of primary cells and cell lines, to a greater degree than D1/2/3 alone, although some cell lines did not respond to TGM1. Ectopic expression of CD44 in nonresponding cells conferred responsiveness, while genetic depletion of CD44 abolished enhancement by D4/5 and ablated the ability of full-length TGM1 to bind to cell surfaces. Moreover, CD44-deficient T cells showed attenuated induction of Foxp3 by full-length TGM1, to levels similar to those induced by D1/2/3. Hence, a parasite protein known to bind two host cytokine receptor subunits has evolved a third receptor specificity, which serves to raise the avidity and cell type–specific potency of TGF-β signaling in mammalian cells.","journal":"Proceedings of the National Academy of Sciences","year":2023,"id":326260,"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":29,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9573,"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":878724,"name":"Kyle T. Cunningham","orcid":"0000-0002-2171-0277","position":1,"is_corresponding":false},{"id":488878,"name":"Shashi Prakash Singh","orcid":"0000-0002-6029-8115","position":2,"is_corresponding":false},{"id":1045162,"name":"Madeleine P. J. White","orcid":"0000-0002-0152-1110","position":3,"is_corresponding":false},{"id":878725,"name":"Tiffany Campion","orcid":"0009-0002-4010-0762","position":4,"is_corresponding":false},{"id":1045828,"name":"Claire Ciancia","orcid":null,"position":5,"is_corresponding":false},{"id":673476,"name":"Peter A. van Veelen","orcid":"0000-0002-7898-9408","position":6,"is_corresponding":false},{"id":673470,"name":"Arnoud H. de Ru","orcid":"0009-0002-1166-4059","position":7,"is_corresponding":false},{"id":251355,"name":"Román González‐Prieto","orcid":"0000-0001-8997-2321","position":8,"is_corresponding":false},{"id":568781,"name":"Ananya Mukundan","orcid":"0000-0003-1161-4158","position":9,"is_corresponding":false},{"id":568782,"name":"Chang‐Hyeock Byeon","orcid":"0000-0001-9997-7708","position":10,"is_corresponding":false},{"id":997101,"name":"Sophia R. Staggers","orcid":"0000-0002-8157-6372","position":11,"is_corresponding":false},{"id":567444,"name":"Cynthia S. Hinck","orcid":"0000-0002-2163-9378","position":12,"is_corresponding":false},{"id":398270,"name":"Andrew P. Hinck","orcid":"0000-0003-3320-8054","position":13,"is_corresponding":false},{"id":702422,"name":"Peter ten Dijke","orcid":"0000-0002-7234-342X","position":14,"is_corresponding":false},{"id":636919,"name":"Rick M. Maizels","orcid":"0000-0003-3216-1944","position":15,"is_corresponding":false},{"id":1045161,"name":"Maarten van Dinther","orcid":"0000-0002-9451-8884","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-19T01:08:33.106703Z","pmid":"37590410","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":[]}