{"doi":"10.17615/62ab-kh85","title":"Receptor Cross-Talk Spatially Restricts p-ERK during TLR4 Stimulation of Autoreactive B Cells","abstract":"To maintain tolerance, autoreactive B cells must regulate signal transduction from the B cell receptor and Toll-like receptors. We recently identified that dendritic cells and macrophages regulate autoreactive cells during TLR4 activation by releasing IL-6 and soluble CD40L (sCD40L). These cytokines selectively repress antibody secretion from autoreactive, but not antigenically naïve, B cells. How IL-6 and sCD40L repress autoantibody production is unknown. In this paper, we show that IL-6 and sCD40L are required for low-affinity/avidity autoreactive B cells to maintain tolerance through a mechanism involving receptor crosstalk between the BCR, TLR4, and the IL-6 receptor or CD40. We show that acute signaling through IL-6 receptor or CD40 integrates with chronic BCR-mediated ERK activation to restrict pERK from the nucleus and repress TLR4-induced Blimp-1 and XBP-1 expression. Tolerance is disrupted in 2-12H/MRL/lpr mice where IL-6 and sCD40L fail to spatially restrict pERK and fail to repress TLR4-induced Ig secretion. In the case of CD40, acute signaling in B cells from 2-12H/MRL/lpr mice is intact, but the chronic activation of pERK emanating from the BCR is attenuated. Re-establishing chronically active ERK through retroviral expression of constitutively active MEK1 restores tolerance upon sCD40L, but not IL-6, stimulation indicating that regulation by IL-6 requires another signaling effector. These data define the molecular basis for the regulation of low-affinity autoreactive B cells during TLR4 stimulation, they explain how autoreactive but not naïve B cells are repressed by IL-6 and sCD40L, and they identify B cell defects in lupus-prone mice that lead to TLR4-induced autoantibody production.","journal":"UNC Libraries","year":2020,"id":143787,"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":0.9465,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":599365,"name":"Kristen N. Krum","orcid":null,"position":1,"is_corresponding":false},{"id":592530,"name":"Shannon Z. Jones","orcid":null,"position":2,"is_corresponding":false},{"id":597156,"name":"Jennifer A. Rutan","orcid":"0000-0002-2272-1234","position":3,"is_corresponding":false},{"id":599366,"name":"Sang Ryul Lee","orcid":null,"position":4,"is_corresponding":false},{"id":546748,"name":"Andrew J. Monteith","orcid":"0000-0002-7259-6574","position":5,"is_corresponding":false},{"id":540830,"name":"SunAh Kang","orcid":"0000-0002-6327-184X","position":6,"is_corresponding":false},{"id":245447,"name":"Jose Roques","orcid":"0000-0002-5783-9531","position":7,"is_corresponding":false},{"id":541448,"name":"Stephen H. Clarke","orcid":null,"position":8,"is_corresponding":false},{"id":275084,"name":"Barbara J. Vilen","orcid":"0000-0003-0014-0022","position":9,"is_corresponding":false},{"id":612282,"name":"Michelle A. Kilmon","orcid":null,"position":10,"is_corresponding":false},{"id":548661,"name":"Nikki J. Wagner","orcid":"0000-0002-4872-3107","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:17:41.821196Z","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":[]}