{"doi":"10.1101/2023.01.23.525206","title":"Failed down-regulation of PI3K signaling makes autoreactive B cells receptive to bystander T cell help","abstract":"The role of T cell help in autoantibody responses is not well understood. Since tolerance mechanisms govern both T and B cell responses, one might predict that both T cell tolerance and B cell tolerance must be defeated in autoantibody responses requiring T cell help. To define whether autoreactive B cells depend on T cells to generate autoantibody responses, we studied the role of T cells in autoantibody responses resulting from acute cell-specific deletion of regulatory phosphatases. Ars/A1 B cells are DNA-reactive and require continuous inhibitory signaling by the tyrosine phosphatase SHP-1 and the inositol phosphatases SHIP-1 and PTEN to maintain unresponsiveness. Acute B cell-restricted deletion of any of these phosphatases results in an autoantibody response. Here we show that CD40-CD40L interactions are required to support autoantibody responses of B cells whose anergy has been compromised. If the B cell-intrinsic driver of loss of tolerance is failed negative regulation of PI3K signaling, bystander T cells provide sufficient CD40-mediated signal 2 to support an autoantibody response. However, while autoantibody responses driven by acute B cell-targeted deletion of SHP-1 also require T cells, bystander T cell help does not suffice. These results demonstrate that upregulation of PI3K signaling in autoreactive B cells, recapitulating the effect of multiple autoimmunity risk alleles, promotes autoantibody responses both by increasing B cells’ cooperation with non-cognate T cell help, as well as by altering BCR signaling. Receptiveness to bystander T cell help enables autoreactive B cells to circumvent the fail-safe of T cell tolerance. Significance: Phosphatase suppression of PI3K signaling is an important mechanism by which peripheral autoreactive B cells are kept in an unresponsive/anergic state. Loss of this suppression, due to genetic alleles that confer risk of autoimmunity, often occurs in autoreactive B cells of individuals who develop autoimmune disease. Here we demonstrate that de-repression of PI3K signaling promotes autoantibody responses of a DNA-reactive B cell clone by relaxing dependence of autoantibody responses on T cell-derived helper signals. These results suggest that impaired regulation of PI3K signaling can promote autoantibody responses in two ways: by restoring antigen receptor signaling and by enabling autoreactive B cells to circumvent restrictions imposed by T cell tolerance mechanisms.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":402572,"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":0.952,"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":411836,"name":"Andrew Getahun","orcid":"0000-0002-5663-6812","position":1,"is_corresponding":false},{"id":1180310,"name":"Brigita E. Fiske","orcid":null,"position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-19T01:20:27.903246Z","pmid":"36747655","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":[]}