{"doi":"10.1126/scisignal.adh0439","title":"Cbl-b mitigates the responsiveness of naive CD8 <sup>+</sup> T cells that experience extensive tonic T cell receptor signaling","abstract":"Naive T cells experience tonic T cell receptor (TCR) signaling in response to self-antigens presented by major histocompatibility complex (MHC) in secondary lymphoid organs. We investigated how relatively weak or strong tonic TCR signals influence naive CD8 + T cell responses to stimulation with foreign antigens. The heterogeneous expression of Nur77-GFP, a transgenic reporter of tonic TCR signaling, in naive CD8 + T cells suggests variable intensities or durations of tonic TCR signaling. Although the expression of genes associated with acutely stimulated T cells was increased in Nur77-GFP HI cells, these cells were hyporesponsive to agonist TCR stimulation compared with Nur77-GFP LO cells. This hyporesponsiveness manifested as diminished activation marker expression and decreased secretion of IFN-γ and IL-2. The protein abundance of the ubiquitin ligase Cbl-b, a negative regulator of TCR signaling, was greater in Nur77-GFP HI cells than in Nur77-GFP LO cells, and Cbl-b deficiency partially restored the responsiveness of Nur77-GFP HI cells. Our data suggest that the cumulative effects of previously experienced tonic TCR signaling recalibrate naive CD8 + T cell responsiveness. These changes include gene expression changes and negative regulation partially dependent on Cbl-b. This cell-intrinsic negative feedback loop may enable the immune system to restrain naive CD8 + T cells with higher self-reactivity.","journal":"Science Signaling","year":2024,"id":434763,"datarank":0.5196162136261484,"base_score":2.5649493574615367,"endowment":2.5649493574615367,"self_citation_contribution":0.38474240361923057,"citation_network_contribution":0.13487381000691778,"self_endowment_contribution":0.38474240361923057,"citer_contribution":0.13487381000691778,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":11,"citers_with_citation_signal":7,"citers_with_endowment":7,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9617,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":837052,"name":"Wendy M. Zinzow-Kramer","orcid":"0000-0003-1469-5803","position":1,"is_corresponding":false},{"id":651873,"name":"Yuesong Hu","orcid":"0000-0002-6528-0491","position":2,"is_corresponding":false},{"id":388821,"name":"Elizabeth Motunrayo Kolawole","orcid":"0000-0003-3138-0037","position":3,"is_corresponding":false},{"id":1040176,"name":"Yuan-Li Tsai","orcid":"0000-0003-2879-9259","position":4,"is_corresponding":false},{"id":344120,"name":"Arthur Weiss","orcid":"0000-0002-2414-9024","position":5,"is_corresponding":false},{"id":388823,"name":"Brian D. Evavold","orcid":"0000-0002-3561-3494","position":6,"is_corresponding":false},{"id":313824,"name":"Khalid Salaita","orcid":"0000-0003-4138-3477","position":7,"is_corresponding":false},{"id":270265,"name":"Christopher D. Scharer","orcid":"0000-0001-7716-8504","position":8,"is_corresponding":false},{"id":722335,"name":"Byron B. Au‐Yeung","orcid":"0000-0002-6446-9102","position":9,"is_corresponding":false},{"id":722334,"name":"Joel Eggert","orcid":"0000-0002-2982-6020","position":0,"is_corresponding":true}],"reference_count":109,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:59:58.582186Z","pmid":"38319998","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":[]}