title: IL-4-secreting secondary T follicular helper (Tfh) cells arise from memory T cells, not persisting Tfh cells, through a B cell-dependent mechanism.
abstract: Humoral immunity requires cross-talk between T follicular helper (Tfh) cells and B cells. Nevertheless, a detailed understanding of this intercellular interaction during secondary immune responses is lacking. We examined this by focusing on the response to a soluble, unadjuvanted, pathogen-derived Ag (soluble extract of Schistosoma mansoni egg [SEA]) that induces type 2 immunity. We found that activated Tfh cells persisted for long periods within germinal centers following primary immunization. However, the magnitude of the secondary response did not appear to depend on pre-existing Tfh cells. Instead, Tfh cell populations expanded through a process that was dependent on memory T cells recruited into the reactive LN, as well as the participation of B cells. We found that, during the secondary response, IL-4 was critical for the expansion of a population of plasmablasts that correlated with increased SEA-specific IgG1 titers. Additionally, following immunization with SEA (but not with an Ag that induced type 1 immunity), IL-4 and IL-21 were coproduced by individual Tfh cells, revealing a potential mechanism through which appropriate class-switching can be coupled to plasmablast proliferation to enforce type 2 immunity. Our findings demonstrate a pivotal role for IL-4 in the interplay between T and B cells during a secondary Th2 response and have significant implications for vaccine design.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110; Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907;
authors.forename: Keke C
authors.initials: KC
authors.lastname: Fairfax
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110; Department of Parasitology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands;
authors.forename: Bart
authors.initials: B
authors.lastname: Everts
authors.affiliation: Department of Medical Laboratory and Radiation Sciences, University of Vermont, Burlington, VT 05405;
authors.forename: Eyal
authors.initials: E
authors.lastname: Amiel
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Amber M
authors.initials: AM
authors.lastname: Smith
authors.affiliation: Research Center Borstel, 23845 Borstel, Germany; and.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schramm
authors.affiliation: Research Center Borstel, 23845 Borstel, Germany; and.
authors.forename: Helmut
authors.initials: H
authors.lastname: Haas
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Gwendalyn J
authors.initials: GJ
authors.lastname: Randolph
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109.
authors.forename: Justin J
authors.initials: JJ
authors.lastname: Taylor
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110; edwardpearce@path.wustl.edu.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Pearce
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D000947:Antigens, Helminth / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D002450:Cell Communication / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D007114:Immunization; D007156:Immunologic Memory; D016130:Immunophenotyping; D015847:Interleukin-4 / Q000378:metabolism*; D007378:Interleukins / Q000096:biosynthesis; D008198:Lymph Nodes / Q000378:metabolism; D008212:Lymphocyte Depletion; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D012550:Schistosoma mansoni / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D000098546:Interleukin-21
chemical_list: D000941:Antigens; D000947:Antigens, Helminth; D007378:Interleukins; D015847:Interleukin-4; D000098546:Interleukin-21