{"doi":"10.1101/2023.03.06.531375","title":"Integration of Avidity and Differentiation is enabled by CD8 <sup>+</sup> T-cell sensing of IFN-γ","abstract":"Abstract The most effective responses to intracellular pathogens have a breadth of T-cell clones with different affinities for their cognate peptide, and a diversity of functional phenotypes, from effector to long-lived memory cells. While high- and low-affinity T-cells are inherently skewed towards becoming effector and memory, respectively, overall, both functional subsets exploit a wide range of affinities. How the breadth of affinities and functionalities are coordinated is therefore unclear. In this study, we provide evidence that direct sensing of the cytokine IFN-γ by CD8 + T-cells is a factor controlling the integration of T-cell affinity and differentiation during infection. IFN-γ increases the expansion of low-affinity T-cells, allowing them to overcome the selective advantage of high-affinity T-cells. Concomitantly, IFN-γ reinforces high-affinity T-cell entry into the memory pool. As a result, direct IFN-γ sensing by CD8 + T-cells increases the avidity of the memory response. This comes at the expense of the primary T-cell response, for which IFN-γ decreases the avidity, leading to sub-optimum immunity to infection. IFN-γ sensing by CD8 + T-cells is paracrine, provided by a distinct subset of CD8 + T-cells called Virtual Memory T-cells, an antigen inexperienced subset that harbors memory features. Overall, we propose that IFN-γ and Virtual Memory T-cells fulfil a critical immunoregulatory role by enabling the coordination of T-cell avidity and fate.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":403561,"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":0.9501,"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":1036250,"name":"Han Cai","orcid":"0009-0007-2242-6984","position":1,"is_corresponding":false},{"id":1036698,"name":"Jagdish N. Mahale","orcid":null,"position":2,"is_corresponding":false},{"id":1036251,"name":"Andrew J. MacLean","orcid":"0009-0008-8378-4141","position":3,"is_corresponding":false},{"id":1036252,"name":"Julie M. Mazet","orcid":"0000-0001-5245-4096","position":4,"is_corresponding":false},{"id":1036700,"name":"Alexander J. He","orcid":null,"position":5,"is_corresponding":false},{"id":1036253,"name":"Doreen Lau","orcid":"0000-0002-7623-2401","position":6,"is_corresponding":false},{"id":292657,"name":"Tim Elliott","orcid":"0000-0003-1097-0222","position":7,"is_corresponding":false},{"id":337032,"name":"Audrey Gérard","orcid":"0000-0003-3059-3065","position":8,"is_corresponding":false},{"id":1036249,"name":"Lion F. K. Uhl","orcid":"0000-0003-1729-9857","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-19T01:20:36.280647Z","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":[]}