{"doi":"10.7554/elife.99389","title":"Follicular helper- and peripheral helper-like T cells drive autoimmune disease in human immune system mice","abstract":"Human immune system (HIS) mice constructed in various ways are widely used for investigations of human immune responses to pathogens, transplants, and immunotherapies. In HIS mice that generate T cells de novo from hematopoietic progenitors, T cell-dependent multisystem autoimmune disease occurs, most rapidly when the human T cells develop in the native NOD.Cg- Prkdc scid Il2rg tm1Wjl (NSG) mouse thymus, where negative selection is abnormal. Disease develops very late when human T cells develop in human fetal thymus grafts, where robust negative selection is observed. We demonstrate here that PD-1 + CD4 + peripheral (Tph) helper-like and follicular (Tfh) helper-like T cells developing in HIS mice can induce autoimmune disease. Tfh-like cells were more prominent in HIS mice with a mouse thymus, in which the highest levels of IgG were detected in plasma, compared to those with a human thymus. While circulating IgG and IgM antibodies were autoreactive to multiple mouse antigens, in vivo depletion of B cells and antibodies did not delay the development of autoimmune disease. Conversely, adoptive transfer of enriched Tfh- or Tph-like cells induced disease and autoimmunity-associated B cell phenotypes in recipient mice containing autologous human APCs without T cells. Tfh/Tph cells from mice with a human thymus expanded and induced disease more rapidly than those originating in a murine thymus, implicating HLA-restricted T cell-APC interactions in this process. Since Tfh, Tph, autoantibodies, and lymphopenia-induced proliferation (LIP) have all been implicated in various forms of human autoimmune disease, the observations here provide a platform for the further dissection of human autoimmune disease mechanisms and therapies.","journal":"eLife","year":2024,"id":488783,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9562,"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":774955,"name":"Andrea Vecchione","orcid":"0000-0002-5497-6856","position":1,"is_corresponding":false},{"id":369804,"name":"Nichole Danzl","orcid":"0000-0002-2340-2577","position":2,"is_corresponding":false},{"id":236117,"name":"Hao Wei Li","orcid":"0009-0005-2894-0293","position":3,"is_corresponding":false},{"id":369803,"name":"Grace Nauman","orcid":"0000-0002-1633-5150","position":4,"is_corresponding":false},{"id":184323,"name":"Rachel Madley","orcid":null,"position":5,"is_corresponding":false},{"id":677331,"name":"Elizabeth Waffarn","orcid":"0000-0001-5484-7344","position":6,"is_corresponding":false},{"id":56237,"name":"Robert Winchester","orcid":"0000-0002-7543-8037","position":7,"is_corresponding":false},{"id":585763,"name":"Amanda Ruiz","orcid":"0000-0002-6404-4905","position":8,"is_corresponding":false},{"id":677533,"name":"Xiaolan Ding","orcid":null,"position":9,"is_corresponding":false},{"id":555439,"name":"Georgia Fousteri","orcid":"0000-0001-7745-7517","position":10,"is_corresponding":false},{"id":369810,"name":"Megan Sykes","orcid":"0000-0002-4947-4376","position":11,"is_corresponding":false},{"id":1333358,"name":"Mohsen Khosravi-Maharlooei","orcid":"0009-0001-2385-3714","position":0,"is_corresponding":true}],"reference_count":39,"raw_metadata":null,"created_at":"2026-07-19T02:08:19.655720Z","pmid":"40293219","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":[]}