title: Human B cells promote T-cell plasticity to optimize antibody response by inducing coexpression of T(H)1/T(FH) signatures.
abstract: BACKGROUND
  B cells mediate humoral immunity against pathogens but also direct CD4(+) T-cell responses. Recent plasticity studies in mice have challenged the concept of strict fate commitment during CD4(+) T-cell differentiation into distinct subsets.
  
  
  OBJECTIVE
  We sought to elucidate the contribution of human antigen-primed B cells in CD4(+) T-cell responses that support humoral immunity.
  
  
  METHODS
  CD4(+) T-cell differentiation by primary human B cells was investigated in in vitro cocultures by using tetanus toxoid and Salmonella species as antigen models. T-cell differentiation was assessed by using intracellular cytokines and subset-specific transcription factors and markers. IgM and IgG formation was analyzed by means of ELISA.
  
  
  RESULTS
  Human B cells, but not dendritic cells, induce prominent and stable coexpression of TH1 and follicular helper T (TFH) cell characteristics during priming and on antigen recall. TH1/TFH cells coexpress the TH1 and TFH effector cytokines IFN-γ and IL-21 and the TFH marker CXCR5, demonstrating that the coexpressed TH1 and TFH subset-specifying transcription factors T-box transcription factor (T-bet) and B cell lymphoma 6 are both functionally active. B cell-derived IL-6 and IL-12 controlled respective expression of IL-21 and IFN-γ, with IL-21 being key for humoral immunity.
  
  
  CONCLUSIONS
  Human B cells exploit CD4(+) T-cell plasticity to create flexibility in the effector T-cell response. Induction of a T-cell subset coexpressing IL-21 and IFN-γ might combine IL-21-mediated T-cell aid for antibody production while maintaining TH1 cytokine expression to support other cellular immune defenses.
authors.affiliation: Department of Immunopathology, Sanquin Blood Supply, Division of Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jelle
authors.initials: J
authors.lastname: de Wit
authors.affiliation: Department of Immunopathology, Sanquin Blood Supply, Division of Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Tineke
authors.initials: T
authors.lastname: Jorritsma
authors.affiliation: Department of Immunopathology, Sanquin Blood Supply, Division of Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Mateusz
authors.initials: M
authors.lastname: Makuch
authors.affiliation: Renal Transplant Unit, Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Ester B M
authors.initials: EBM
authors.lastname: Remmerswaal
authors.affiliation: Department of Immunopathology, Sanquin Blood Supply, Division of Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Hanny
authors.initials: H
authors.lastname: Klaasse Bos
authors.affiliation: Department of Immunopathology, Sanquin Blood Supply, Division of Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Souwer
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Jacques
authors.initials: J
authors.lastname: Neefjes
authors.affiliation: Renal Transplant Unit, Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Ineke J M
authors.initials: IJM
authors.lastname: Ten Berge
authors.affiliation: Department of Immunopathology, Sanquin Blood Supply, Division of Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: m.vanham@sanquin.nl.
authors.forename: S Marieke
authors.initials: SM
authors.lastname: van Ham
mesh_terms: D000917:Antibody Formation; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation; D005786:Gene Expression Regulation; D006801:Humans; D007156:Immunologic Memory; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D010641:Phenotype; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D059467:Transcriptome; D000098546:Interleukin-21
chemical_list: D007378:Interleukins; D007371:Interferon-gamma; D000098546:Interleukin-21
keywords: B cell; Bcl-6; IFN-γ; IL-21; T-bet; T-cell plasticity; antibody response; coexpression; crosstalk