{"doi":"10.1101/2021.03.13.435273","title":"PD-1 dependent expansion of Amphregulin <sup>+</sup> FOXP3 <sup>+</sup> cells is associated with oral immune dysfunction in HIV patients on therapy","abstract":"Abstract Residual systemic inflammation and mucosal immune dysfunction persist in people living with HIV (PLWH) despite treatment with combined anti-retroviral therapy (cART), but the underlying immune mechanisms are poorly understood. Here we report an altered immune landscape involving upregulation of TLR- and inflammasome signaling, localized CD4 + T cell hyperactivation, and counterintuitively, an enrichment of CD4 + CD25 + FOXP3 + regulatory T cells (T regs ) in the oral mucosa of HIV + patients on therapy. Using human oral tonsil cultures, we found that HIV infection causes an increase in a unique population of FOXP3 + cells expressing PD-1, IFN-γ, Amphiregulin (AREG), and IL-10. These cells persisted even in the presence of the anti-retroviral drug and underwent further expansion driven by TLR-2 ligands and IL-1β. IL-1β also promoted PD-1 upregulation in AKT1 dependent manner. PD-1 stabilized FOXP3 and AREG expression in these cells through a mechanism requiring the activation of Asparaginyl Endopeptidase (AEP). Importantly, these FOXP3 + cells were incapable of suppressing CD4 + T cells in vitro . Concurrently, HIV + patients harbored higher levels of PD-1, IFN-γ, Amphiregulin (AREG), and IL-10 expressing FOXP3 + cells, which strongly correlated with CD4 + T cell hyperactivation, suggesting an absence of CD4 + T cell regulation in the oral mucosa. Taken together, this study provides insights into a novel mechanism of FOXP3 + cell dysregulation and reveals a critical link in the positive feedback loop of oral mucosal immune activation events in HIV + patients on therapy. One Sentence Summary HIV-induced immune dysfunction in lymphoid and mucosal tissues","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":223632,"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":0.9558,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":340874,"name":"Elizabeth Schneider","orcid":null,"position":1,"is_corresponding":false},{"id":339585,"name":"Fady Faddoul","orcid":"0000-0002-0055-3719","position":2,"is_corresponding":false},{"id":340873,"name":"Andre Paes da Silva","orcid":null,"position":3,"is_corresponding":false},{"id":750450,"name":"Robert Asaad","orcid":null,"position":4,"is_corresponding":false},{"id":644925,"name":"Aarthi Talla","orcid":"0000-0002-4971-3322","position":5,"is_corresponding":false},{"id":750451,"name":"Neil S. Greenspan","orcid":null,"position":6,"is_corresponding":false},{"id":825476,"name":"AD Levine","orcid":null,"position":7,"is_corresponding":false},{"id":36269,"name":"David McDonald","orcid":"0000-0002-2410-9364","position":8,"is_corresponding":false},{"id":456187,"name":"Jonathan Karn","orcid":"0000-0002-2900-094X","position":9,"is_corresponding":false},{"id":825477,"name":"M. M. Lederman","orcid":null,"position":10,"is_corresponding":false},{"id":339589,"name":"Pushpa Pandiyan","orcid":"0000-0003-3688-0794","position":11,"is_corresponding":false},{"id":825475,"name":"Nimesh Bhaskaran","orcid":null,"position":0,"is_corresponding":true}],"reference_count":89,"raw_metadata":null,"created_at":"2026-07-18T23:54:11.061295Z","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":[]}