{"doi":"10.1101/2021.09.27.462076","title":"PD-1 checkpoint blockade activates germinal center follicular T cell programs that disrupt type 2 isotype-specific antibody homeostasis","abstract":"ABSTRACT Multiple CD4 T cell dependent tolerance mechanisms control adaptive B cell immunity to environmental antigens. We recently demonstrated a PD-1 checkpoint within steady-state splenic germinal centers (GC) that constrains the maturation of type 2 IgG1 isotype-specific antibody homeostasis. Here, we utilized single cell-indexed custom RNA-sequencing to probe the follicular T cell mechanisms directly targeted by acute PD-1 blockade. We find a pre-existing subset of follicular helper T (T FH ) cells that express type 2 immune response properties (T FH 2) with exaggerated pathways of TCR activation, cytokine signaling, and enhanced cell-cell contact upon acute PD-1 blockade. This selective amplification of the T FH 2 program significantly increases predicted molecular connections to type 2 IgG1 GC B cells that dominate limited changes in GC localized follicular regulatory T (GC T FR ) cell programs. These studies demonstrate how type 2 isotype-specific adaptive B cell tolerance is selectively disrupted by acute PD-1 blockade to reveal the modular regulatory mechanisms that control splenic GC dynamics at homeostasis. One Sentence Summary Acute PD-1 blockade alters the regulatory dynamic of the steady state germinal center to drive the maturation of IgG1 GC B cells towards PC differentiation in a process mediated by type 2 like TFH effector molecules. HIGHLIGHTS - Acute PD-1 blockade enhances the steady state splenic TFH program - PD-1 blockade selectively exaggerates a Type 2 like TFH module - GC TFR cells are minimally impacted by blockade - PD-1 restrains predicted TFH2 functional contacts with IgG1 GC B Cells","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":221773,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9522,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":809348,"name":"Brett Higgins","orcid":"0000-0003-2006-6704","position":1,"is_corresponding":false},{"id":781414,"name":"Karen B. Miller","orcid":"0000-0002-6572-5745","position":2,"is_corresponding":false},{"id":781418,"name":"Louise J. McHeyzer‐Williams","orcid":"0000-0002-8860-2983","position":3,"is_corresponding":false},{"id":781419,"name":"Michael G. McHeyzer‐Williams","orcid":"0000-0003-0459-569X","position":4,"is_corresponding":false},{"id":781412,"name":"Andrew G. Shuparski","orcid":"0000-0002-3703-0890","position":0,"is_corresponding":true}],"reference_count":79,"raw_metadata":null,"created_at":"2026-07-18T23:53:59.302331Z","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":[]}