{"doi":"10.4049/jimmunol.2300683","title":"CD4 T Cell–Derived IL-21 Is Critical for Sustaining <i>Plasmodium</i> Infection–Induced Germinal Center Responses and Promoting the Selection of Memory B Cells with Recall Potential","abstract":"Development of Plasmodium-specific humoral immunity is critically dependent on CD4 Th cell responses and germinal center (GC) reactions during blood-stage Plasmodium infection. IL-21, a cytokine primarily produced by CD4 T cells, is an essential regulator of affinity maturation, isotype class-switching, B cell differentiation, and maintenance of GC reactions in response to many infection and immunization models. In models of experimental malaria, mice deficient in IL-21 or its receptor IL-21R fail to develop memory B cell populations and are not protected against secondary infection. However, whether sustained IL-21 signaling in ongoing GCs is required for maintaining GC magnitude, organization, and output is unclear. In this study, we report that CD4+ Th cells maintain IL-21 expression after resolution of primary Plasmodium yoelii infection. We generated an inducible knockout mouse model that enabled cell type-specific and timed deletion of IL-21 in peripheral, mature CD4 T cells. We found that persistence of IL-21 signaling in active GCs had no impact on the magnitude of GC reactions or their capacity to produce memory B cell populations. However, the memory B cells generated in the absence of IL-21 exhibited reduced recall function upon challenge. Our data support that IL-21 prevents premature cellular dissolution within the GC and promotes stringency of selective pressures during B cell fate determination required to produce high-quality Plasmodium-specific memory B cells. These data are additionally consistent with a temporal requirement for IL-21 in fine-tuning humoral immune memory responses during experimental malaria.","journal":"The Journal of Immunology","year":2024,"id":475513,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9548,"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":272849,"name":"Fionna A. Surette","orcid":null,"position":1,"is_corresponding":false},{"id":1193125,"name":"Graham Ausdal","orcid":null,"position":2,"is_corresponding":false},{"id":1312541,"name":"Manan Shah","orcid":"0000-0003-1390-5450","position":3,"is_corresponding":false},{"id":972160,"name":"Allen M. Minns","orcid":"0000-0003-1500-2802","position":4,"is_corresponding":false},{"id":514873,"name":"Scott E. Lindner","orcid":"0000-0003-1799-3726","position":5,"is_corresponding":false},{"id":302502,"name":"Ryan Zander","orcid":"0000-0002-7431-8535","position":6,"is_corresponding":false},{"id":271045,"name":"Noah S. Butler","orcid":"0000-0002-1429-0796","position":7,"is_corresponding":false},{"id":715804,"name":"Jordan T. Johnson","orcid":"0000-0001-5585-321X","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-19T02:06:21.071690Z","pmid":"38477614","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":[]}