{"doi":"10.3389/fimmu.2024.1360219","title":"Human regulatory memory B cells defined by expression of TIM-1 and TIGIT are dysfunctional in multiple sclerosis","abstract":"Background: Regulatory B cells (Bregs) play a pivotal role in suppressing immune responses, yet there is still a lack of cell surface markers that can rigorously identify them. In mouse models for multiple sclerosis (MS), TIM-1 or TIGIT expression on B cells is required for maintaining self-tolerance and regulating autoimmunity to the central nervous system. Here we investigated the activities of human memory B cells that differentially express TIM-1 and TIGIT to determine their potential regulatory function in healthy donors and patients with relapsing-remitting (RR) MS. Methods: FACS-sorted TIM-1+/-TIGIT+/- memory B (memB) cells co-cultured with allogenic CD4+ T cells were analyzed for proliferation and induction of inflammatory markers using flow cytometry and cytokine quantification, to determine Th1/Th17 cell differentiation. Transcriptional differences were assessed by SMARTSeq2 RNA sequencing analysis. Results: TIM-1-TIGIT- double negative (DN) memB cells strongly induce T cell proliferation and pro-inflammatory cytokine expression. The TIM-1+ memB cells enabled low levels of CD4+ T cell activation and gave rise to T cells that co-express IL-10 with IFNγ and IL-17A or FoxP3. T cells cultured with the TIM-1+TIGIT+ double positive (DP) memB cells exhibited reduced proliferation and IFNγ, IL-17A, TNFα, and GM-CSF expression, and exhibited strong regulation in Breg suppression assays. The functional activity suggests the DP memB cells are a bonafide Breg population. However, MS DP memB cells were less inhibitory than HC DP memB cells. A retrospective longitudinal study of anti-CD20 treated patients found that post-treatment DP memB cell frequency and absolute number were associated with response to therapy. Transcriptomic analyses indicated that the dysfunctional MS-derived DP memB/Breg population exhibited increased expression of genes associated with T cell activation and survival (CD80, ZNF10, PIK3CA), and had distinct gene expression compared to the TIGIT+ or TIM-1+ memB cells. Conclusion: These findings demonstrate that TIM-1/TIGIT expressing memory B cell subsets have distinct functionalities. Co-expression of TIM-1 and TIGIT defines a regulatory memory B cell subset that is functionally impaired in MS.","journal":"Frontiers in Immunology","year":2024,"id":431564,"datarank":0.4335557636844247,"base_score":2.8903717578961645,"endowment":2.8903717578961645,"self_citation_contribution":0.4335557636844247,"citation_network_contribution":0.0,"self_endowment_contribution":0.4335557636844247,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":17,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.961,"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":1235840,"name":"Belinda J. Kaskow","orcid":"0000-0003-3132-4924","position":1,"is_corresponding":false},{"id":1126902,"name":"Felipe von Glehn","orcid":"0000-0002-1004-7641","position":2,"is_corresponding":false},{"id":1236290,"name":"Junning Case","orcid":null,"position":3,"is_corresponding":false},{"id":1235841,"name":"Zhenhua Li","orcid":"0000-0002-1075-0214","position":4,"is_corresponding":false},{"id":307494,"name":"Amélie M. Julé","orcid":"0000-0003-2605-6726","position":5,"is_corresponding":false},{"id":1206016,"name":"Emma L. Berdan","orcid":"0000-0002-6435-4604","position":6,"is_corresponding":false},{"id":255850,"name":"Shannan J. Ho Sui","orcid":"0000-0002-6191-4709","position":7,"is_corresponding":false},{"id":1235842,"name":"Yong Hu","orcid":"0000-0002-7721-9268","position":8,"is_corresponding":false},{"id":778306,"name":"Rajesh Krishnan","orcid":"0000-0002-9171-3422","position":9,"is_corresponding":false},{"id":289232,"name":"Tanuja Chitnis","orcid":"0000-0002-9897-4422","position":10,"is_corresponding":false},{"id":6940,"name":"Vijay K. Kuchroo","orcid":"0000-0001-7177-2110","position":11,"is_corresponding":false},{"id":7840,"name":"Howard L. Weiner","orcid":"0000-0003-0203-9681","position":12,"is_corresponding":false},{"id":902682,"name":"Clare Baecher‐Allan","orcid":"0000-0003-2405-8525","position":13,"is_corresponding":false},{"id":1235839,"name":"Johnna F. Varghese","orcid":"0000-0001-9152-2880","position":0,"is_corresponding":true}],"reference_count":72,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:59:30.747263Z","pmid":"38745667","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":[]}