{"doi":"10.1101/2025.10.06.680719","title":"Impaired IFNγ responsiveness of monocyte-derived lung cells limits immunity to <i>Mycobacterium tuberculosis</i>","abstract":"Abstract Lung mononuclear phagocyte (MNP) subsets differ in their ability to restrict Mycobacterium tuberculosis (Mtb) during chronic infection, yet the mechanisms underlying this difference are not well defined. Here, we show that CD11c lo monocyte-derived cells (MNC1), the subset of lung cells that is most permissive for Mtb viability during chronic infection, express lower levels of interferon-gamma (IFNγ) signaling proteins, resulting in reduced responses to IFNγ compared to alveolar macrophages (AM) and CD11c hi MNC2. Moreover, type I IFN signaling suppresses IFNγ-mediated MHC-II expression, impairing antigen-specific CD4 T cell activation by MNC1 cells. Importantly, prior immunity conferred by contained Mtb infection enhances IFNγ responsiveness of monocyte-derived cells, reducing bacterial burdens in lungs and within MNC subsets. Our findings indicate that heterogeneous IFNγ responsiveness is exploited by Mtb for persistence in vivo. Overcoming or bypassing impaired IFNγ responsiveness may guide the development of more effective TB vaccines and host-directed therapies.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":577027,"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":0.9578,"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":650951,"name":"Jason Limberis","orcid":"0000-0002-7893-8416","position":1,"is_corresponding":false},{"id":424364,"name":"Zachary P. Howard","orcid":"0000-0002-1958-4638","position":2,"is_corresponding":false},{"id":1331884,"name":"Alexander Mohapatra","orcid":"0000-0003-0400-6146","position":3,"is_corresponding":false},{"id":884416,"name":"Enzo Takagi","orcid":"0000-0002-2625-686X","position":4,"is_corresponding":false},{"id":8685,"name":"J. Ernst","orcid":"0000-0001-9951-6207","position":5,"is_corresponding":false},{"id":560242,"name":"Weihao Zheng","orcid":"0000-0002-8038-1207","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-19T02:58:00.620755Z","pmid":"41279172","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":[]}