{"doi":"10.1101/2025.04.17.648233","title":"Neuropilin-2 functions as a co-inhibitory receptor to regulate antigen-induced inflammation and allograft rejection","abstract":"Abstract Co-inhibitory receptors function as central modulators of the immune response to resolve T effector activation and/or to sustain immune homeostasis. Here, using humanized SCID mice, we found that NRP2 is inducible on late effector and exhausted subsets of human CD4 + T cells and that it is co-expressed with established co-inhibitory molecules including PD-1, CTLA4, TIGIT, LAG3 and TIM3. In murine models, we also found that NRP2 is expressed on effector memory CD4 + T cells with an exhausted phenotype and that it functions as a key co-inhibitory molecule. Knockout of NRP2 resulted in hyperactive CD4 + T cell responses, and enhanced inflammation in delayed type hypersensitivity and transplantation models. Following cardiac transplantation, allograft rejection and graft failure was accelerated in global as well as CD4 + T cell-specific knockout recipients, and enhanced alloimmunity was dependent on NRP2 expression on CD4 + T effectors, and not on CD4 + Foxp3 + T regulatory cells. Also, knockout T regulatory cells were found to be as efficient as wild type cells in the suppression of effector responses in vitro and in vivo. These collective findings identify NRP2 as a novel coinhibitory receptor and demonstrate that its expression on CD4 + T effector cells is of great functional importance in immunity.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":564655,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9615,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1468332,"name":"Nora Kochupurakkal","orcid":null,"position":1,"is_corresponding":false},{"id":96018,"name":"Sek Won Kong","orcid":"0000-0003-4877-7567","position":2,"is_corresponding":false},{"id":1467936,"name":"Sayantan Bose","orcid":"0000-0001-6413-2019","position":3,"is_corresponding":false},{"id":375756,"name":"Ji‐Won Lee","orcid":"0000-0002-2666-4249","position":4,"is_corresponding":false},{"id":1468333,"name":"Madeline Maslyar","orcid":null,"position":5,"is_corresponding":false},{"id":1468334,"name":"Bayan Alsairafi","orcid":null,"position":6,"is_corresponding":false},{"id":823521,"name":"Kay F. Macleod","orcid":"0000-0002-8995-4155","position":7,"is_corresponding":false},{"id":734869,"name":"Kaifeng Liu","orcid":"0009-0003-0157-8349","position":8,"is_corresponding":false},{"id":447943,"name":"Hengcheng Zhang","orcid":"0000-0002-2562-1247","position":9,"is_corresponding":false},{"id":1468335,"name":"Masaki Komatsu","orcid":null,"position":10,"is_corresponding":false},{"id":935066,"name":"Hironao Nakayama","orcid":"0000-0002-9371-2650","position":11,"is_corresponding":false},{"id":474667,"name":"Diane R. Bielenberg","orcid":"0000-0003-3905-0059","position":12,"is_corresponding":false},{"id":734870,"name":"David M. Briscoe","orcid":"0000-0003-4135-5417","position":13,"is_corresponding":false},{"id":734868,"name":"Johannes Wedel","orcid":"0000-0002-3490-8477","position":0,"is_corresponding":true}],"reference_count":90,"raw_metadata":null,"created_at":"2026-07-19T02:56:24.872312Z","pmid":null,"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":[]}